DNA Damage/Telomere Stress Induced Senescence (Homo sapiens)

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4, 8, 18, 22, 35...38, 74, 10222, 5844, 137, 1409, 14, 95, 97, 10826, 28, 73, 1468, 38, 434364, 66, 69, 13328, 38, 435826, 28, 73, 124, 14635, 778, 2235, 77, 11811, 26, 38, 53, 70...7, 1838, 439, 10, 21, 58, 89...cytosolnucleoplasmCDK2 p-S15-TP53Tetramer:CDKN1AGeneDNA double-strand break ends EP400:p-S15-TP53Tetramer:CDKN1AGeneHIST1H1C HIST1H2BO CCNA1 RAD50 HIST3H2BB NBN H2AFX RAD50 RAD50 Oxidative StressInduced SenescenceHIST1H2BD HIST2H2BE DNA Double StrandBreak ResponseMRE11A ATM NBN HIST1H1B CoA-SHHIST1H2AC HIST1H2BB RAD50 CCNA:CDK2HIST1H2BC KAT5 RAD50 HIST1H4 CDKN1B RB1proton HIST1H1D CDKN1A geneDNADSBs:MRN:Ac-K3016-ATM dimer:KAT5HIST1H2BL RAD50 DNADSBs:MRN:p-S1981,Ac-K3016-ATM:KAT5H2AFJ Shelterin complexCDKN1A CCNA1 HIST1H1A KAT5 ATPRAD50 Ac-K3016-ATM POT1 HIST3H3 CDK2 NBN HIST1H2BN Shortened telomereX-ray DNA DSBs:MRNEP400Oncogenic MAPKsignalingHMGA2ATM TP53 CABIN1NBN Extended AndProcessed TelomereEnd and AssociatedDNA Binding andPackaging ProteinComplex Folded IntoHigher OrderStructureCCNA2 Intrinsic Pathwayfor ApoptosisTERF2 HIST1H2BA Histone H1 boundchromatin DNAATM CDK2 ROS MRE11A Ac-K3016-ATM gamma-ray Shortenedtelomere:MRN:Ac-K3016-ATM dimer:KAT5dsDNACDKN1A DNA double-strandbreak endsHMGA1 HIRA KAT5 POT1 ACD UBN1H2BFS p-S15-TP53 KAT5 Ac-CoAp-S15-TP53 TERF2IP Mitotic G1-G1/SphasesHIST1H1D MRE11A CyclinE:CDK2:CDKN1A,CDKN1BCCNE:CDK2ATPH2AFB1 MRE11A HIRAKAT5 UBN1 CDKN1A DNA double-strand break ends UBN1 CABIN1 DNA double-strand break ends CDKN1AShortenedtelomere:MRN:ATMdimer:KAT5beta-particle NBN CDKN1A gene Shortened telomere p-S15-TP53 TetramerCell CycleCheckpointsp-S1981,Ac-K3016-ATMTINF2 alpha-particle H1F0 CCNE1 Shortened telomere HIRA CDKN1A,CDKN1BNBN ASF1A CDKN1B DNA double-strand break ends MRE11A HIST1H2AB H2AFZ HIST1H1B CDKN1B Shortenedtelomere:MRN:KAT5:p-S1981,Ac-K3016-ATMTERF2 MRE11A ADPDNA DSBs:MRN:ATMdimer:KAT5SAHFHMGA2 HIST1H2AJ p-S1981,Ac-K3016-ATM ASF1AHistone H1TERF1 Shortened telomere HIST1H1C HMGA1NBN RAD50 Senescence-Associated Secretory Phenotype (SASP)EP400 ASF1A DNA POT1KAT5 LMNB1CDKN1A gene Shortened telomere MRE11A TINF2 CCNE2 TERF2IP MRNHIST2H2AA3 CCNE2 MRE11A HIST2H2AC ADPp-S1981,Ac-K3016-ATM CDK2 CyclinA:Cdk2:p21/p27complexATM dimer:KAT5NBN CCNE1 CCNA2 HIST1H2BJ HIST1H2BH p-S15-TP53 Shortenedtelomere:MRNH1F0 MRE11A HIST1H1E HIST1H2BK ligated C-strand Okazaki fragment RAD50 DSB inducing agentsNBN Oncogene InducedSenescenceHIST1H2BM ATPCABIN1 HIST1H1E TERF1 HIRA:ASF1A:UBN1:CABIN1G-strand Chromosome end with two additional single strand repeats and a subterminal loop - Telomeric TP53 TetramerACD H2AFV HIST1H1A ADPKAT5 HIST1H2AD DNA 38, 4322383, 62, 75, 101, 117...281085817, 19, 23, 33, 37...2, 12, 27, 34, 46...30, 83, 98143251, 4-6, 15...4313, 20, 24, 39, 41...


Reactive oxygen species (ROS), whose concentration increases in senescent cells due to oncogenic RAS-induced mitochondrial dysfunction (Moiseeva et al. 2009) or due to environmental stress, cause DNA damage in the form of double strand breaks (DSBs) (Yu and Anderson 1997). In addition, persistent cell division fueled by oncogenic signaling leads to replicative exhaustion, manifested in critically short telomeres (Harley et al. 1990, Hastie et al. 1990). Shortened telomeres are no longer able to bind the protective shelterin complex (Smogorzewska et al. 2000, de Lange 2005) and are recognized as damaged DNA.

The evolutionarily conserved MRN complex, consisting of MRE11A (MRE11), RAD50 and NBN (NBS1) subunits, binds DSBs (Lee and Paull 2005) and shortened telomeres that are no longer protected by shelterin (Wu et al. 2007). Once bound to the DNA, the MRN complex recruits and activates ATM kinase (Lee and Paull 2005, Wu et al. 2007), leading to phosphorylation of ATM targets, including TP53 (p53) (Banin et al. 1998, Canman et al. 1998, Khanna et al. 1998). TP53, phosphorylated on serine S15 by ATM, binds the CDKN1A (also known as p21, CIP1 or WAF1) promoter and induces CDKN1A transcription (El-Deiry et al. 1993, Karlseder et al. 1999). CDKN1A inhibits the activity of CDK2, leading to G1/S cell cycle arrest (Harper et al. 1993, El-Deiry et al. 1993).<p>SMURF2 is upregulated in response to telomere attrition in human fibroblasts and induces senecscent phenotype through RB1 and TP53, independently of its role in TGF-beta-1 signaling (Zhang and Cohen 2004). The exact mechanism of SMURF2 involvement is senescence has not been elucidated. View original pathway at:Reactome.</div>


Pathway is converted from Reactome ID: 2559586
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Reactome Author: Orlic-Milacic, Marija

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  1. Kuzmichev A, Nishioka K, Erdjument-Bromage H, Tempst P, Reinberg D.; ''Histone methyltransferase activity associated with a human multiprotein complex containing the Enhancer of Zeste protein.''; PubMed Europe PMC
  2. Yang BS, Hauser CA, Henkel G, Colman MS, Van Beveren C, Stacey KJ, Hume DA, Maki RA, Ostrowski MC.; ''Ras-mediated phosphorylation of a conserved threonine residue enhances the transactivation activities of c-Ets1 and c-Ets2.''; PubMed Europe PMC
  3. Samatar AA, Poulikakos PI.; ''Targeting RAS-ERK signalling in cancer: promises and challenges.''; PubMed Europe PMC
  4. Moiseeva O, Bourdeau V, Roux A, Deschênes-Simard X, Ferbeyre G.; ''Mitochondrial dysfunction contributes to oncogene-induced senescence.''; PubMed Europe PMC
  5. Moiseeva O, Mallette FA, Mukhopadhyay UK, Moores A, Ferbeyre G.; ''DNA damage signaling and p53-dependent senescence after prolonged beta-interferon stimulation.''; PubMed Europe PMC
  6. Meng W, Swenson LL, Fitzgibbon MJ, Hayakawa K, Ter Haar E, Behrens AE, Fulghum JR, Lippke JA.; ''Structure of mitogen-activated protein kinase-activated protein (MAPKAP) kinase 2 suggests a bifunctional switch that couples kinase activation with nuclear export.''; PubMed Europe PMC
  7. Curtin NJ.; ''DNA repair dysregulation from cancer driver to therapeutic target.''; PubMed Europe PMC
  8. Karlseder J, Broccoli D, Dai Y, Hardy S, de Lange T.; ''p53- and ATM-dependent apoptosis induced by telomeres lacking TRF2.''; PubMed Europe PMC
  9. Zhang R, Chen W, Adams PD.; ''Molecular dissection of formation of senescence-associated heterochromatin foci.''; PubMed Europe PMC
  10. Narita M, Narita M, Krizhanovsky V, Nuñez S, Chicas A, Hearn SA, Myers MP, Lowe SW.; ''A novel role for high-mobility group a proteins in cellular senescence and heterochromatin formation.''; PubMed Europe PMC
  11. Uziel T, Lerenthal Y, Moyal L, Andegeko Y, Mittelman L, Shiloh Y.; ''Requirement of the MRN complex for ATM activation by DNA damage.''; PubMed Europe PMC
  12. Le Gallic L, Virgilio L, Cohen P, Biteau B, Mavrothalassitis G.; ''ERF nuclear shuttling, a continuous monitor of Erk activity that links it to cell cycle progression.''; PubMed Europe PMC
  13. Parry D, Bates S, Mann DJ, Peters G.; ''Lack of cyclin D-Cdk complexes in Rb-negative cells correlates with high levels of p16INK4/MTS1 tumour suppressor gene product.''; PubMed Europe PMC
  14. Banumathy G, Somaiah N, Zhang R, Tang Y, Hoffmann J, Andrake M, Ceulemans H, Schultz D, Marmorstein R, Adams PD.; ''Human UBN1 is an ortholog of yeast Hpc2p and has an essential role in the HIRA/ASF1a chromatin-remodeling pathway in senescent cells.''; PubMed Europe PMC
  15. White A, Pargellis CA, Studts JM, Werneburg BG, Farmer BT.; ''Molecular basis of MAPK-activated protein kinase 2:p38 assembly.''; PubMed Europe PMC
  16. Agger K, Cloos PA, Rudkjaer L, Williams K, Andersen G, Christensen J, Helin K.; ''The H3K27me3 demethylase JMJD3 contributes to the activation of the INK4A-ARF locus in response to oncogene- and stress-induced senescence.''; PubMed Europe PMC
  17. Bailly S, Fay M, Israël N, Gougerot-Pocidalo MA.; ''The transcription factor AP-1 binds to the human interleukin 1 alpha promoter.''; PubMed Europe PMC
  18. Yu TW, Anderson D.; ''Reactive oxygen species-induced DNA damage and its modification: a chemical investigation.''; PubMed Europe PMC
  19. Rodier F, Coppé JP, Patil CK, Hoeijmakers WA, Muñoz DP, Raza SR, Freund A, Campeau E, Davalos AR, Campisi J.; ''Persistent DNA damage signalling triggers senescence-associated inflammatory cytokine secretion.''; PubMed Europe PMC
  20. Guan KL, Jenkins CW, Li Y, O'Keefe CL, Noh S, Wu X, Zariwala M, Matera AG, Xiong Y.; ''Isolation and characterization of p19INK4d, a p16-related inhibitor specific to CDK6 and CDK4.''; PubMed Europe PMC
  21. Sadaie M, Salama R, Carroll T, Tomimatsu K, Chandra T, Young AR, Narita M, Pérez-Mancera PA, Bennett DC, Chong H, Kimura H, Narita M.; ''Redistribution of the Lamin B1 genomic binding profile affects rearrangement of heterochromatic domains and SAHF formation during senescence.''; PubMed Europe PMC
  22. el-Deiry WS, Tokino T, Velculescu VE, Levy DB, Parsons R, Trent JM, Lin D, Mercer WE, Kinzler KW, Vogelstein B.; ''WAF1, a potential mediator of p53 tumor suppression.''; PubMed Europe PMC
  23. Atwood AA, Sealy LJ.; ''C/EBPβ's role in determining Ras-induced senescence or transformation.''; PubMed Europe PMC
  24. Depoortere F, Van Keymeulen A, Lukas J, Costagliola S, Bartkova J, Dumont JE, Bartek J, Roger PP, Dremier S.; ''A requirement for cyclin D3-cyclin-dependent kinase (cdk)-4 assembly in the cyclic adenosine monophosphate-dependent proliferation of thyrocytes.''; PubMed Europe PMC
  25. Ciccia A, Elledge SJ.; ''The DNA damage response: making it safe to play with knives.''; PubMed Europe PMC
  26. Sun Y, Xu Y, Roy K, Price BD.; ''DNA damage-induced acetylation of lysine 3016 of ATM activates ATM kinase activity.''; PubMed Europe PMC
  27. Malumbres M, Pérez De Castro I, Hernández MI, Jiménez M, Corral T, Pellicer A.; ''Cellular response to oncogenic ras involves induction of the Cdk4 and Cdk6 inhibitor p15(INK4b).''; PubMed Europe PMC
  28. Sun Y, Jiang X, Chen S, Fernandes N, Price BD.; ''A role for the Tip60 histone acetyltransferase in the acetylation and activation of ATM.''; PubMed Europe PMC
  29. New L, Jiang Y, Han J.; ''Regulation of PRAK subcellular location by p38 MAP kinases.''; PubMed Europe PMC
  30. Saelens X, Festjens N, Vande Walle L, van Gurp M, van Loo G, Vandenabeele P.; ''Toxic proteins released from mitochondria in cell death.''; PubMed Europe PMC
  31. Ichijo H, Nishida E, Irie K, ten Dijke P, Saitoh M, Moriguchi T, Takagi M, Matsumoto K, Miyazono K, Gotoh Y.; ''Induction of apoptosis by ASK1, a mammalian MAPKKK that activates SAPK/JNK and p38 signaling pathways.''; PubMed Europe PMC
  32. Takekawa M, Tatebayashi K, Saito H.; ''Conserved docking site is essential for activation of mammalian MAP kinase kinases by specific MAP kinase kinase kinases.''; PubMed Europe PMC
  33. Acosta JC, O'Loghlen A, Banito A, Guijarro MV, Augert A, Raguz S, Fumagalli M, Da Costa M, Brown C, Popov N, Takatsu Y, Melamed J, d'Adda di Fagagna F, Bernard D, Hernando E, Gil J.; ''Chemokine signaling via the CXCR2 receptor reinforces senescence.''; PubMed Europe PMC
  34. Zhang Y, Xiong Y, Yarbrough WG.; ''ARF promotes MDM2 degradation and stabilizes p53: ARF-INK4a locus deletion impairs both the Rb and p53 tumor suppression pathways.''; PubMed Europe PMC
  35. Harper JW, Adami GR, Wei N, Keyomarsi K, Elledge SJ.; ''The p21 Cdk-interacting protein Cip1 is a potent inhibitor of G1 cyclin-dependent kinases.''; PubMed Europe PMC
  36. Okazaki K, Sagata N.; ''The Mos/MAP kinase pathway stabilizes c-Fos by phosphorylation and augments its transforming activity in NIH 3T3 cells.''; PubMed Europe PMC
  37. Matsusaka T, Fujikawa K, Nishio Y, Mukaida N, Matsushima K, Kishimoto T, Akira S.; ''Transcription factors NF-IL6 and NF-kappa B synergistically activate transcription of the inflammatory cytokines, interleukin 6 and interleukin 8.''; PubMed Europe PMC
  38. Lee JH, Paull TT.; ''ATM activation by DNA double-strand breaks through the Mre11-Rad50-Nbs1 complex.''; PubMed Europe PMC
  39. Sadasivam S, DeCaprio JA.; ''The DREAM complex: master coordinator of cell cycle-dependent gene expression.''; PubMed Europe PMC
  40. Ben-Levy R, Leighton IA, Doza YN, Attwood P, Morrice N, Marshall CJ, Cohen P.; ''Identification of novel phosphorylation sites required for activation of MAPKAP kinase-2.''; PubMed Europe PMC
  41. Connell-Crowley L, Harper JW, Goodrich DW.; ''Cyclin D1/Cdk4 regulates retinoblastoma protein-mediated cell cycle arrest by site-specific phosphorylation.''; PubMed Europe PMC
  42. Hannon GJ, Beach D.; ''p15INK4B is a potential effector of TGF-beta-induced cell cycle arrest.''; PubMed Europe PMC
  43. Wu Y, Xiao S, Zhu XD.; ''MRE11-RAD50-NBS1 and ATM function as co-mediators of TRF1 in telomere length control.''; PubMed Europe PMC
  44. Khanna KK, Keating KE, Kozlov S, Scott S, Gatei M, Hobson K, Taya Y, Gabrielli B, Chan D, Lees-Miller SP, Lavin MF.; ''ATM associates with and phosphorylates p53: mapping the region of interaction.''; PubMed Europe PMC
  45. Cheng M, Sexl V, Sherr CJ, Roussel MF.; ''Assembly of cyclin D-dependent kinase and titration of p27Kip1 regulated by mitogen-activated protein kinase kinase (MEK1).''; PubMed Europe PMC
  46. To KH, Pajovic S, Gallie BL, Thériault BL.; ''Regulation of p14ARF expression by miR-24: a potential mechanism compromising the p53 response during retinoblastoma development.''; PubMed Europe PMC
  47. Ferreira R, Magnaghi-Jaulin L, Robin P, Harel-Bellan A, Trouche D.; ''The three members of the pocket proteins family share the ability to repress E2F activity through recruitment of a histone deacetylase.''; PubMed Europe PMC
  48. Clifton AD, Young PR, Cohen P.; ''A comparison of the substrate specificity of MAPKAP kinase-2 and MAPKAP kinase-3 and their activation by cytokines and cellular stress.''; PubMed Europe PMC
  49. Sgouras DN, Athanasiou MA, Beal GJ, Fisher RJ, Blair DG, Mavrothalassitis GJ.; ''ERF: an ETS domain protein with strong transcriptional repressor activity, can suppress ets-associated tumorigenesis and is regulated by phosphorylation during cell cycle and mitogenic stimulation.''; PubMed Europe PMC
  50. Cobrinik D.; ''Pocket proteins and cell cycle control.''; PubMed Europe PMC
  51. Orjalo AV, Bhaumik D, Gengler BK, Scott GK, Campisi J.; ''Cell surface-bound IL-1alpha is an upstream regulator of the senescence-associated IL-6/IL-8 cytokine network.''; PubMed Europe PMC
  52. Serrano M, Hannon GJ, Beach D.; ''A new regulatory motif in cell-cycle control causing specific inhibition of cyclin D/CDK4.''; PubMed Europe PMC
  53. Bakkenist CJ, Kastan MB.; ''DNA damage activates ATM through intermolecular autophosphorylation and dimer dissociation.''; PubMed Europe PMC
  54. Gao Z, Zhang J, Bonasio R, Strino F, Sawai A, Parisi F, Kluger Y, Reinberg D.; ''PCGF homologs, CBX proteins, and RYBP define functionally distinct PRC1 family complexes.''; PubMed Europe PMC
  55. Senturk S, Mumcuoglu M, Gursoy-Yuzugullu O, Cingoz B, Akcali KC, Ozturk M.; ''Transforming growth factor-beta induces senescence in hepatocellular carcinoma cells and inhibits tumor growth.''; PubMed Europe PMC
  56. Raingeaud J, Whitmarsh AJ, Barrett T, Dérijard B, Davis RJ.; ''MKK3- and MKK6-regulated gene expression is mediated by the p38 mitogen-activated protein kinase signal transduction pathway.''; PubMed Europe PMC
  57. Fleming Y, Armstrong CG, Morrice N, Paterson A, Goedert M, Cohen P.; ''Synergistic activation of stress-activated protein kinase 1/c-Jun N-terminal kinase (SAPK1/JNK) isoforms by mitogen-activated protein kinase kinase 4 (MKK4) and MKK7.''; PubMed Europe PMC
  58. Chan HM, Narita M, Lowe SW, Livingston DM.; ''The p400 E1A-associated protein is a novel component of the p53 --> p21 senescence pathway.''; PubMed Europe PMC
  59. Nicke B, Bastien J, Khanna SJ, Warne PH, Cowling V, Cook SJ, Peters G, Delpuech O, Schulze A, Berns K, Mullenders J, Beijersbergen RL, Bernards R, Ganesan TS, Downward J, Hancock DC.; ''Involvement of MINK, a Ste20 family kinase, in Ras oncogene-induced growth arrest in human ovarian surface epithelial cells.''; PubMed Europe PMC
  60. Lukas SM, Kroe RR, Wildeson J, Peet GW, Frego L, Davidson W, Ingraham RH, Pargellis CA, Labadia ME, Werneburg BG.; ''Catalysis and function of the p38 alpha.MK2a signaling complex.''; PubMed Europe PMC
  61. Dietrich N, Bracken AP, Trinh E, Schjerling CK, Koseki H, Rappsilber J, Helin K, Hansen KH.; ''Bypass of senescence by the polycomb group protein CBX8 through direct binding to the INK4A-ARF locus.''; PubMed Europe PMC
  62. Lito P, Rosen N, Solit DB.; ''Tumor adaptation and resistance to RAF inhibitors.''; PubMed Europe PMC
  63. Foulds CE, Nelson ML, Blaszczak AG, Graves BJ.; ''Ras/mitogen-activated protein kinase signaling activates Ets-1 and Ets-2 by CBP/p300 recruitment.''; PubMed Europe PMC
  64. Harley CB, Futcher AB, Greider CW.; ''Telomeres shorten during ageing of human fibroblasts.''; PubMed Europe PMC
  65. Matsuura H, Nishitoh H, Takeda K, Matsuzawa A, Amagasa T, Ito M, Yoshioka K, Ichijo H.; ''Phosphorylation-dependent scaffolding role of JSAP1/JIP3 in the ASK1-JNK signaling pathway. A new mode of regulation of the MAP kinase cascade.''; PubMed Europe PMC
  66. Hastie ND, Dempster M, Dunlop MG, Thompson AM, Green DK, Allshire RC.; ''Telomere reduction in human colorectal carcinoma and with ageing.''; PubMed Europe PMC
  67. Seidel JJ, Graves BJ.; ''An ERK2 docking site in the Pointed domain distinguishes a subset of ETS transcription factors.''; PubMed Europe PMC
  68. Barradas M, Anderton E, Acosta JC, Li S, Banito A, Rodriguez-Niedenführ M, Maertens G, Banck M, Zhou MM, Walsh MJ, Peters G, Gil J.; ''Histone demethylase JMJD3 contributes to epigenetic control of INK4a/ARF by oncogenic RAS.''; PubMed Europe PMC
  69. de Lange T.; ''Shelterin: the protein complex that shapes and safeguards human telomeres.''; PubMed Europe PMC
  70. Kozlov SV, Graham ME, Peng C, Chen P, Robinson PJ, Lavin MF.; ''Involvement of novel autophosphorylation sites in ATM activation.''; PubMed Europe PMC
  71. Chien Y, Scuoppo C, Wang X, Fang X, Balgley B, Bolden JE, Premsrirut P, Luo W, Chicas A, Lee CS, Kogan SC, Lowe SW.; ''Control of the senescence-associated secretory phenotype by NF-κB promotes senescence and enhances chemosensitivity.''; PubMed Europe PMC
  72. Zhang H.; ''Life without kinase: cyclin E promotes DNA replication licensing and beyond.''; PubMed Europe PMC
  73. Sun Y, Jiang X, Xu Y, Ayrapetov MK, Moreau LA, Whetstine JR, Price BD.; ''Histone H3 methylation links DNA damage detection to activation of the tumour suppressor Tip60.''; PubMed Europe PMC
  74. Lisby M, Barlow JH, Burgess RC, Rothstein R.; ''Choreography of the DNA damage response: spatiotemporal relationships among checkpoint and repair proteins.''; PubMed Europe PMC
  75. Prior IA, Lewis PD, Mattos C.; ''A comprehensive survey of Ras mutations in cancer.''; PubMed Europe PMC
  76. Vijayachandra K, Lee J, Glick AB.; ''Smad3 regulates senescence and malignant conversion in a mouse multistage skin carcinogenesis model.''; PubMed Europe PMC
  77. Montagnoli A, Fiore F, Eytan E, Carrano AC, Draetta GF, Hershko A, Pagano M.; ''Ubiquitination of p27 is regulated by Cdk-dependent phosphorylation and trimeric complex formation.''; PubMed Europe PMC
  78. McLaughlin MM, Kumar S, McDonnell PC, Van Horn S, Lee JC, Livi GP, Young PR.; ''Identification of mitogen-activated protein (MAP) kinase-activated protein kinase-3, a novel substrate of CSBP p38 MAP kinase.''; PubMed Europe PMC
  79. Nelson ML, Kang HS, Lee GM, Blaszczak AG, Lau DK, McIntosh LP, Graves BJ.; ''Ras signaling requires dynamic properties of Ets1 for phosphorylation-enhanced binding to coactivator CBP.''; PubMed Europe PMC
  80. Chellappan SP, Hiebert S, Mudryj M, Horowitz JM, Nevins JR.; ''The E2F transcription factor is a cellular target for the RB protein.''; PubMed Europe PMC
  81. Young AR, Narita M.; ''SASP reflects senescence.''; PubMed Europe PMC
  82. Chittenden T, Livingston DM, Kaelin WG.; ''The T/E1A-binding domain of the retinoblastoma product can interact selectively with a sequence-specific DNA-binding protein.''; PubMed Europe PMC
  83. Salvesen GS, Duckett CS.; ''IAP proteins: blocking the road to death's door.''; PubMed Europe PMC
  84. Wajapeyee N, Serra RW, Zhu X, Mahalingam M, Green MR.; ''Oncogenic BRAF induces senescence and apoptosis through pathways mediated by the secreted protein IGFBP7.''; PubMed Europe PMC
  85. Coppé JP, Patil CK, Rodier F, Sun Y, Muñoz DP, Goldstein J, Nelson PS, Desprez PY, Campisi J.; ''Senescence-associated secretory phenotypes reveal cell-nonautonomous functions of oncogenic RAS and the p53 tumor suppressor.''; PubMed Europe PMC
  86. Ainbinder E, Bergelson S, Pinkus R, Daniel V.; ''Regulatory mechanisms involved in activator-protein-1 (AP-1)-mediated activation of glutathione-S-transferase gene expression by chemical agents.''; PubMed Europe PMC
  87. Agherbi H, Gaussmann-Wenger A, Verthuy C, Chasson L, Serrano M, Djabali M.; ''Polycomb mediated epigenetic silencing and replication timing at the INK4a/ARF locus during senescence.''; PubMed Europe PMC
  88. Lees JA, Saito M, Vidal M, Valentine M, Look T, Harlow E, Dyson N, Helin K.; ''The retinoblastoma protein binds to a family of E2F transcription factors.''; PubMed Europe PMC
  89. Funayama R, Saito M, Tanobe H, Ishikawa F.; ''Loss of linker histone H1 in cellular senescence.''; PubMed Europe PMC
  90. Guan KL, Jenkins CW, Li Y, Nichols MA, Wu X, O'Keefe CL, Matera AG, Xiong Y.; ''Growth suppression by p18, a p16INK4/MTS1- and p14INK4B/MTS2-related CDK6 inhibitor, correlates with wild-type pRb function.''; PubMed Europe PMC
  91. Goodarzi AA, Jonnalagadda JC, Douglas P, Young D, Ye R, Moorhead GB, Lees-Miller SP, Khanna KK.; ''Autophosphorylation of ataxia-telangiectasia mutated is regulated by protein phosphatase 2A.''; PubMed Europe PMC
  92. Deacon K, Blank JL.; ''Characterization of the mitogen-activated protein kinase kinase 4 (MKK4)/c-Jun NH2-terminal kinase 1 and MKK3/p38 pathways regulated by MEK kinases 2 and 3. MEK kinase 3 activates MKK3 but does not cause activation of p38 kinase in vivo.''; PubMed Europe PMC
  93. Lin TY, Cheng YC, Yang HC, Lin WC, Wang CC, Lai PL, Shieh SY.; ''Loss of the candidate tumor suppressor BTG3 triggers acute cellular senescence via the ERK-JMJD3-p16(INK4a) signaling axis.''; PubMed Europe PMC
  94. Fang S, Jensen JP, Ludwig RL, Vousden KH, Weissman AM.; ''Mdm2 is a RING finger-dependent ubiquitin protein ligase for itself and p53.''; PubMed Europe PMC
  95. Ye X, Zerlanko B, Zhang R, Somaiah N, Lipinski M, Salomoni P, Adams PD.; ''Definition of pRB- and p53-dependent and -independent steps in HIRA/ASF1a-mediated formation of senescence-associated heterochromatin foci.''; PubMed Europe PMC
  96. Jimi E, Ikebe T, Takahashi N, Hirata M, Suda T, Koga T.; ''Interleukin-1 alpha activates an NF-kappaB-like factor in osteoclast-like cells.''; PubMed Europe PMC
  97. Zhang R, Poustovoitov MV, Ye X, Santos HA, Chen W, Daganzo SM, Erzberger JP, Serebriiskii IG, Canutescu AA, Dunbrack RL, Pehrson JR, Berger JM, Kaufman PD, Adams PD.; ''Formation of MacroH2A-containing senescence-associated heterochromatin foci and senescence driven by ASF1a and HIRA.''; PubMed Europe PMC
  98. Wang X.; ''The expanding role of mitochondria in apoptosis.''; PubMed Europe PMC
  99. Bracken AP, Kleine-Kohlbrecher D, Dietrich N, Pasini D, Gargiulo G, Beekman C, Theilgaard-Mönch K, Minucci S, Porse BT, Marine JC, Hansen KH, Helin K.; ''The Polycomb group proteins bind throughout the INK4A-ARF locus and are disassociated in senescent cells.''; PubMed Europe PMC
  100. Andegeko Y, Moyal L, Mittelman L, Tsarfaty I, Shiloh Y, Rotman G.; ''Nuclear retention of ATM at sites of DNA double strand breaks.''; PubMed Europe PMC
  101. Lavoie H, Therrien M.; ''Regulation of RAF protein kinases in ERK signalling.''; PubMed Europe PMC
  102. Shroff R, Arbel-Eden A, Pilch D, Ira G, Bonner WM, Petrini JH, Haber JE, Lichten M.; ''Distribution and dynamics of chromatin modification induced by a defined DNA double-strand break.''; PubMed Europe PMC
  103. Fuchs SY, Adler V, Buschmann T, Wu X, Ronai Z.; ''Mdm2 association with p53 targets its ubiquitination.''; PubMed Europe PMC
  104. Vidal A, Koff A.; ''Cell-cycle inhibitors: three families united by a common cause.''; PubMed Europe PMC
  105. Atwood AA, Sealy L.; ''Regulation of C/EBPbeta1 by Ras in mammary epithelial cells and the role of C/EBPbeta1 in oncogene-induced senescence.''; PubMed Europe PMC
  106. Hartupee J, Li X, Hamilton T.; ''Interleukin 1alpha-induced NFkappaB activation and chemokine mRNA stabilization diverge at IRAK1.''; PubMed Europe PMC
  107. Bagchi S, Weinmann R, Raychaudhuri P.; ''The retinoblastoma protein copurifies with E2F-I, an E1A-regulated inhibitor of the transcription factor E2F.''; PubMed Europe PMC
  108. Rai TS, Puri A, McBryan T, Hoffman J, Tang Y, Pchelintsev NA, van Tuyn J, Marmorstein R, Schultz DC, Adams PD.; ''Human CABIN1 is a functional member of the human HIRA/UBN1/ASF1a histone H3.3 chaperone complex.''; PubMed Europe PMC
  109. Acosta JC, Banito A, Wuestefeld T, Georgilis A, Janich P, Morton JP, Athineos D, Kang TW, Lasitschka F, Andrulis M, Pascual G, Morris KJ, Khan S, Jin H, Dharmalingam G, Snijders AP, Carroll T, Capper D, Pritchard C, Inman GJ, Longerich T, Sansom OJ, Benitah SA, Zender L, Gil J.; ''A complex secretory program orchestrated by the inflammasome controls paracrine senescence.''; PubMed Europe PMC
  110. Lee JH, Paull TT.; ''Direct activation of the ATM protein kinase by the Mre11/Rad50/Nbs1 complex.''; PubMed Europe PMC
  111. Quelle DE, Zindy F, Ashmun RA, Sherr CJ.; ''Alternative reading frames of the INK4a tumor suppressor gene encode two unrelated proteins capable of inducing cell cycle arrest.''; PubMed Europe PMC
  112. New L, Jiang Y, Zhao M, Liu K, Zhu W, Flood LJ, Kato Y, Parry GC, Han J.; ''PRAK, a novel protein kinase regulated by the p38 MAP kinase.''; PubMed Europe PMC
  113. Murphy LO, Smith S, Chen RH, Fingar DC, Blenis J.; ''Molecular interpretation of ERK signal duration by immediate early gene products.''; PubMed Europe PMC
  114. Hiebert SW.; ''Regions of the retinoblastoma gene product required for its interaction with the E2F transcription factor are necessary for E2 promoter repression and pRb-mediated growth suppression.''; PubMed Europe PMC
  115. Niehof M, Streetz K, Rakemann T, Bischoff SC, Manns MP, Horn F, Trautwein C.; ''Interleukin-6-induced tethering of STAT3 to the LAP/C/EBPbeta promoter suggests a new mechanism of transcriptional regulation by STAT3.''; PubMed Europe PMC
  116. Nakajima T, Kinoshita S, Sasagawa T, Sasaki K, Naruto M, Kishimoto T, Akira S.; ''Phosphorylation at threonine-235 by a ras-dependent mitogen-activated protein kinase cascade is essential for transcription factor NF-IL6.''; PubMed Europe PMC
  117. Pylayeva-Gupta Y, Grabocka E, Bar-Sagi D.; ''RAS oncogenes: weaving a tumorigenic web.''; PubMed Europe PMC
  118. Wang W, Nacusi L, Sheaff RJ, Liu X.; ''Ubiquitination of p21Cip1/WAF1 by SCFSkp2: substrate requirement and ubiquitination site selection.''; PubMed Europe PMC
  119. Parisi T, Pollice A, Di Cristofano A, Calabrò V, La Mantia G.; ''Transcriptional regulation of the human tumor suppressor p14(ARF) by E2F1, E2F2, E2F3, and Sp1-like factors.''; PubMed Europe PMC
  120. Mizukami Y, Yoshioka K, Morimoto S, Yoshida K.; ''A novel mechanism of JNK1 activation. Nuclear translocation and activation of JNK1 during ischemia and reperfusion.''; PubMed Europe PMC
  121. Weinmann AS, Bartley SM, Zhang T, Zhang MQ, Farnham PJ.; ''Use of chromatin immunoprecipitation to clone novel E2F target promoters.''; PubMed Europe PMC
  122. Kuilman T, Michaloglou C, Vredeveld LC, Douma S, van Doorn R, Desmet CJ, Aarden LA, Mooi WJ, Peeper DS.; ''Oncogene-induced senescence relayed by an interleukin-dependent inflammatory network.''; PubMed Europe PMC
  123. Saitoh M, Nishitoh H, Fujii M, Takeda K, Tobiume K, Sawada Y, Kawabata M, Miyazono K, Ichijo H.; ''Mammalian thioredoxin is a direct inhibitor of apoptosis signal-regulating kinase (ASK) 1.''; PubMed Europe PMC
  124. Koering CE, Pollice A, Zibella MP, Bauwens S, Puisieux A, Brunori M, Brun C, Martins L, Sabatier L, Pulitzer JF, Gilson E.; ''Human telomeric position effect is determined by chromosomal context and telomeric chromatin integrity.''; PubMed Europe PMC
  125. Glover JN, Harrison SC.; ''Crystal structure of the heterodimeric bZIP transcription factor c-Fos-c-Jun bound to DNA.''; PubMed Europe PMC
  126. Wu X, Bayle JH, Olson D, Levine AJ.; ''The p53-mdm-2 autoregulatory feedback loop.''; PubMed Europe PMC
  127. Voncken JW, Niessen H, Neufeld B, Rennefahrt U, Dahlmans V, Kubben N, Holzer B, Ludwig S, Rapp UR.; ''MAPKAP kinase 3pK phosphorylates and regulates chromatin association of the polycomb group protein Bmi1.''; PubMed Europe PMC
  128. Erickson S, Sangfelt O, Heyman M, Castro J, Einhorn S, Grandér D.; ''Involvement of the Ink4 proteins p16 and p15 in T-lymphocyte senescence.''; PubMed Europe PMC
  129. Lal A, Kim HH, Abdelmohsen K, Kuwano Y, Pullmann R, Srikantan S, Subrahmanyam R, Martindale JL, Yang X, Ahmed F, Navarro F, Dykxhoorn D, Lieberman J, Gorospe M.; ''p16(INK4a) translation suppressed by miR-24.''; PubMed Europe PMC
  130. Lee S, Shuman JD, Guszczynski T, Sakchaisri K, Sebastian T, Copeland TD, Miller M, Cohen MS, Taunton J, Smart RC, Xiao Z, Yu LR, Veenstra TD, Johnson PF.; ''RSK-mediated phosphorylation in the C/EBP{beta} leucine zipper regulates DNA binding, dimerization, and growth arrest activity.''; PubMed Europe PMC
  131. Takahashi A, Imai Y, Yamakoshi K, Kuninaka S, Ohtani N, Yoshimoto S, Hori S, Tachibana M, Anderton E, Takeuchi T, Shinkai Y, Peters G, Saya H, Hara E.; ''DNA damage signaling triggers degradation of histone methyltransferases through APC/C(Cdh1) in senescent cells.''; PubMed Europe PMC
  132. Sun P, Yoshizuka N, New L, Moser BA, Li Y, Liao R, Xie C, Chen J, Deng Q, Yamout M, Dong MQ, Frangou CG, Yates JR, Wright PE, Han J.; ''PRAK is essential for ras-induced senescence and tumor suppression.''; PubMed Europe PMC
  133. Smogorzewska A, van Steensel B, Bianchi A, Oelmann S, Schaefer MR, Schnapp G, de Lange T.; ''Control of human telomere length by TRF1 and TRF2.''; PubMed Europe PMC
  134. Maertens O, Cichowski K.; ''An expanding role for RAS GTPase activating proteins (RAS GAPs) in cancer.''; PubMed Europe PMC
  135. Ohtani N, Zebedee Z, Huot TJ, Stinson JA, Sugimoto M, Ohashi Y, Sharrocks AD, Peters G, Hara E.; ''Opposing effects of Ets and Id proteins on p16INK4a expression during cellular senescence.''; PubMed Europe PMC
  136. Sithanandam G, Latif F, Duh FM, Bernal R, Smola U, Li H, Kuzmin I, Wixler V, Geil L, Shrestha S.; ''3pK, a new mitogen-activated protein kinase-activated protein kinase located in the small cell lung cancer tumor suppressor gene region.''; PubMed Europe PMC
  137. Banin S, Moyal L, Shieh S, Taya Y, Anderson CW, Chessa L, Smorodinsky NI, Prives C, Reiss Y, Shiloh Y, Ziv Y.; ''Enhanced phosphorylation of p53 by ATM in response to DNA damage.''; PubMed Europe PMC
  138. Kotake Y, Cao R, Viatour P, Sage J, Zhang Y, Xiong Y.; ''pRB family proteins are required for H3K27 trimethylation and Polycomb repression complexes binding to and silencing p16INK4alpha tumor suppressor gene.''; PubMed Europe PMC
  139. Zhang H, Cohen SN.; ''Smurf2 up-regulation activates telomere-dependent senescence.''; PubMed Europe PMC
  140. Canman CE, Lim DS, Cimprich KA, Taya Y, Tamai K, Sakaguchi K, Appella E, Kastan MB, Siliciano JD.; ''Activation of the ATM kinase by ionizing radiation and phosphorylation of p53.''; PubMed Europe PMC
  141. Stephen AG, Esposito D, Bagni RK, McCormick F.; ''Dragging ras back in the ring.''; PubMed Europe PMC
  142. Wu L, Timmers C, Maiti B, Saavedra HI, Sang L, Chong GT, Nuckolls F, Giangrande P, Wright FA, Field SJ, Greenberg ME, Orkin S, Nevins JR, Robinson ML, Leone G.; ''The E2F1-3 transcription factors are essential for cellular proliferation.''; PubMed Europe PMC
  143. Hupp TR, Lane DP.; ''Allosteric activation of latent p53 tetramers.''; PubMed Europe PMC
  144. Bracken AP, Pasini D, Capra M, Prosperini E, Colli E, Helin K.; ''EZH2 is downstream of the pRB-E2F pathway, essential for proliferation and amplified in cancer.''; PubMed Europe PMC
  145. Du F, Zhang M, Li X, Yang C, Meng H, Wang D, Chang S, Xu Y, Price B, Sun Y.; ''Dimer monomer transition and dimer re-formation play important role for ATM cellular function during DNA repair.''; PubMed Europe PMC
  146. Ayoub N, Jeyasekharan AD, Bernal JA, Venkitaraman AR.; ''HP1-beta mobilization promotes chromatin changes that initiate the DNA damage response.''; PubMed Europe PMC


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101425view11:30, 1 November 2018ReactomeTeamreactome version 66
100963view21:07, 31 October 2018ReactomeTeamreactome version 65
100500view19:41, 31 October 2018ReactomeTeamreactome version 64
100046view16:25, 31 October 2018ReactomeTeamreactome version 63
99598view14:59, 31 October 2018ReactomeTeamreactome version 62 (2nd attempt)
93864view13:41, 16 August 2017ReactomeTeamreactome version 61
93429view11:23, 9 August 2017ReactomeTeamreactome version 61
87144view18:53, 18 July 2016MkutmonOntology Term : 'DNA damage response pathway' added !
86520view09:20, 11 July 2016ReactomeTeamreactome version 56
83455view12:26, 18 November 2015ReactomeTeamNew pathway

External references


View all...
NameTypeDatabase referenceComment
ACD ProteinQ96AP0 (Uniprot-TrEMBL)
ADPMetaboliteCHEBI:16761 (ChEBI)
ASF1A ProteinQ9Y294 (Uniprot-TrEMBL)
ASF1AProteinQ9Y294 (Uniprot-TrEMBL)
ATM ProteinQ13315 (Uniprot-TrEMBL)
ATM dimer:KAT5ComplexR-HSA-5682037 (Reactome)
ATPMetaboliteCHEBI:15422 (ChEBI)
Ac-CoAMetaboliteCHEBI:15351 (ChEBI)
Ac-K3016-ATM ProteinQ13315 (Uniprot-TrEMBL)
CABIN1 ProteinQ9Y6J0 (Uniprot-TrEMBL)
CABIN1ProteinQ9Y6J0 (Uniprot-TrEMBL)
CCNA1 ProteinP78396 (Uniprot-TrEMBL)
CCNA2 ProteinP20248 (Uniprot-TrEMBL)
CCNA:CDK2ComplexR-HSA-141608 (Reactome)
CCNE1 ProteinP24864 (Uniprot-TrEMBL)
CCNE2 ProteinO96020 (Uniprot-TrEMBL)
CCNE:CDK2ComplexR-HSA-68374 (Reactome)
CDK2 ProteinP24941 (Uniprot-TrEMBL)
CDKN1A ProteinP38936 (Uniprot-TrEMBL)
CDKN1A gene ProteinENSG00000124762 (Ensembl)
CDKN1A geneGeneProductENSG00000124762 (Ensembl)
CDKN1A,CDKN1BComplexR-HSA-182558 (Reactome)
CDKN1AProteinP38936 (Uniprot-TrEMBL)
CDKN1B ProteinP46527 (Uniprot-TrEMBL)
Cell Cycle CheckpointsPathwayR-HSA-69620 (Reactome) A hallmark of the human cell cycle in normal somatic cells is its precision. This remarkable fidelity is achieved by a number of signal transduction pathways, known as checkpoints, which monitor cell cycle progression ensuring an interdependency of S-phase and mitosis, the integrity of the genome and the fidelity of chromosome segregation.

Checkpoints are layers of control that act to delay CDK activation when defects in the division program occur. As the CDKs functioning at different points in the cell cycle are regulated by different means, the various checkpoints differ in the biochemical mechanisms by which they elicit their effect. However, all checkpoints share a common hierarchy of a sensor, signal transducers, and effectors that interact with the CDKs.

The stability of the genome in somatic cells contrasts to the almost universal genomic instability of tumor cells. There are a number of documented genetic lesions in checkpoint genes, or in cell cycle genes themselves, which result either directly in cancer or in a predisposition to certain cancer types. Indeed, restraint over cell cycle progression and failure to monitor genome integrity are likely prerequisites for the molecular evolution required for the development of a tumor. Perhaps most notable amongst these is the p53 tumor suppressor gene, which is mutated in >50% of human tumors. Thus, the importance of the checkpoint pathways to human biology is clear.

CoA-SHMetaboliteCHEBI:15346 (ChEBI)


ComplexR-HSA-187926 (Reactome)
Cyclin E:CDK2:CDKN1A,CDKN1BComplexR-HSA-68376 (Reactome)
DNA DSBs:MRN:Ac-K3016-ATM dimer:KAT5ComplexR-HSA-5682035 (Reactome)
DNA DSBs:MRN:p-S1981,Ac-K3016-ATM:KAT5ComplexR-HSA-5682055 (Reactome)
DNA DSBs:MRN:ATM dimer:KAT5ComplexR-HSA-3785779 (Reactome)
DNA DSBs:MRNComplexR-HSA-3785763 (Reactome)
DNA Double Strand Break ResponsePathwayR-HSA-5693606 (Reactome) DNA double strand break (DSB) response involves sensing of DNA DSBs by the MRN complex which triggers ATM activation. ATM phosphorylates a number of proteins involved in DNA damage checkpoint signaling, as well as proteins directly involved in the repair of DNA DSBs. For a recent review, please refer to Ciccia and Elledge, 2010.
DNA R-ALL-29428 (Reactome)
DNA double-strand break endsR-ALL-75165 (Reactome)
DNA double-strand break ends R-ALL-75165 (Reactome)
DSB inducing agentsComplexR-ALL-6783909 (Reactome)
EP400 ProteinQ96L91 (Uniprot-TrEMBL)


ComplexR-HSA-4647605 (Reactome)
EP400ProteinQ96L91 (Uniprot-TrEMBL)
Extended And

Processed Telomere End and Associated DNA Binding and Packaging Protein Complex Folded Into Higher Order

ComplexR-HSA-182751 (Reactome)
G-strand Chromosome end with two additional single strand repeats and a subterminal loop - Telomeric R-HSA-182791 (Reactome)
H1F0 ProteinP07305 (Uniprot-TrEMBL)
H2AFB1 ProteinP0C5Y9 (Uniprot-TrEMBL)
H2AFJ ProteinQ9BTM1 (Uniprot-TrEMBL)
H2AFV ProteinQ71UI9 (Uniprot-TrEMBL)
H2AFX ProteinP16104 (Uniprot-TrEMBL)
H2AFZ ProteinP0C0S5 (Uniprot-TrEMBL)
H2BFS ProteinP57053 (Uniprot-TrEMBL)
HIRA ProteinP54198 (Uniprot-TrEMBL)
HIRA:ASF1A:UBN1:CABIN1ComplexR-HSA-3878132 (Reactome)
HIRAProteinP54198 (Uniprot-TrEMBL)
HIST1H1A ProteinQ02539 (Uniprot-TrEMBL)
HIST1H1B ProteinP16401 (Uniprot-TrEMBL)
HIST1H1C ProteinP16403 (Uniprot-TrEMBL)
HIST1H1D ProteinP16402 (Uniprot-TrEMBL)
HIST1H1E ProteinP10412 (Uniprot-TrEMBL)
HIST1H2AB ProteinP04908 (Uniprot-TrEMBL)
HIST1H2AC ProteinQ93077 (Uniprot-TrEMBL)
HIST1H2AD ProteinP20671 (Uniprot-TrEMBL)
HIST1H2AJ ProteinQ99878 (Uniprot-TrEMBL)
HIST1H2BA ProteinQ96A08 (Uniprot-TrEMBL)
HIST1H2BB ProteinP33778 (Uniprot-TrEMBL)
HIST1H2BC ProteinP62807 (Uniprot-TrEMBL)
HIST1H2BD ProteinP58876 (Uniprot-TrEMBL)
HIST1H2BH ProteinQ93079 (Uniprot-TrEMBL)
HIST1H2BJ ProteinP06899 (Uniprot-TrEMBL)
HIST1H2BK ProteinO60814 (Uniprot-TrEMBL)
HIST1H2BL ProteinQ99880 (Uniprot-TrEMBL)
HIST1H2BM ProteinQ99879 (Uniprot-TrEMBL)
HIST1H2BN ProteinQ99877 (Uniprot-TrEMBL)
HIST1H2BO ProteinP23527 (Uniprot-TrEMBL)
HIST1H4 ProteinP62805 (Uniprot-TrEMBL)
HIST2H2AA3 ProteinQ6FI13 (Uniprot-TrEMBL)
HIST2H2AC ProteinQ16777 (Uniprot-TrEMBL)
HIST2H2BE ProteinQ16778 (Uniprot-TrEMBL)
HIST3H2BB ProteinQ8N257 (Uniprot-TrEMBL)
HIST3H3 ProteinQ16695 (Uniprot-TrEMBL)
HMGA1 ProteinP17096 (Uniprot-TrEMBL)
HMGA1ProteinP17096 (Uniprot-TrEMBL)
HMGA2 ProteinP52926 (Uniprot-TrEMBL)
HMGA2ProteinP52926 (Uniprot-TrEMBL)
Histone H1 bound chromatin DNAComplexR-HSA-211238 (Reactome)
Histone H1ComplexR-HSA-211243 (Reactome)
Intrinsic Pathway for ApoptosisPathwayR-HSA-109606 (Reactome) The intrinsic (Bcl-2 inhibitable or mitochondrial) pathway of apoptosis functions in response to various types of intracellular stress including growth factor withdrawal, DNA damage, unfolding stresses in the endoplasmic reticulum and death receptor stimulation. Following the reception of stress signals, proapoptotic BCL-2 family proteins are activated and subsequently interact with and inactivate antiapoptotic BCL-2 proteins. This interaction leads to the destabilization of the mitochondrial membrane and release of apoptotic factors. These factors induce the caspase proteolytic cascade, chromatin condensation, and DNA fragmentation, ultimately leading to cell death. The key players in the Intrinsic pathway are the Bcl-2 family of proteins that are critical death regulators residing immediately upstream of mitochondria. The Bcl-2 family consists of both anti- and proapoptotic members that possess conserved alpha-helices with sequence conservation clustered in BCL-2 Homology (BH) domains. Proapoptotic members are organized as follows:

1. "Multidomain" BAX family proteins such as BAX, BAK etc. that display sequence conservation in their BH1-3 regions. These proteins act downstream in mitochondrial disruption.

2. "BH3-only" proteins such as BID,BAD, NOXA, PUMA,BIM, and BMF have only the short BH3 motif. These act upstream in the pathway, detecting developmental death cues or intracellular damage. Anti-apoptotic members like Bcl-2, Bcl-XL and their relatives exhibit homology in all segments BH1-4. One of the critical functions of BCL-2/BCL-XL proteins is to maintain the integrity of the mitochondrial outer membrane.

KAT5 ProteinQ92993 (Uniprot-TrEMBL)
LMNB1ProteinP20700 (Uniprot-TrEMBL)
MRE11A ProteinP49959 (Uniprot-TrEMBL)
MRNComplexR-HSA-75164 (Reactome)
Mitotic G1-G1/S phasesPathwayR-HSA-453279 (Reactome) Mitotic G1-G1/S phase involves G1 phase of the mitotic interphase and G1/S transition, when a cell commits to DNA replication and divison genetic and cellular material to two daughter cells.

During early G1, cells can enter a quiescent G0 state. In quiescent cells, the evolutionarily conserved DREAM complex, consisting of the pocket protein family member p130 (RBL2), bound to E2F4 or E2F5, and the MuvB complex, represses transcription of cell cycle genes (reviewed by Sadasivam and DeCaprio 2013).

During early G1 phase in actively cycling cells, transcription of cell cycle genes is repressed by another pocket protein family member, p107 (RBL1), which forms a complex with E2F4 (Ferreira et al. 1998, Cobrinik 2005). RB1 tumor suppressor, the product of the retinoblastoma susceptibility gene, is the third member of the pocket protein family. RB1 binds to E2F transcription factors E2F1, E2F2 and E2F3 and inhibits their transcriptional activity, resulting in prevention of G1/S transition (Chellappan et al. 1991, Bagchi et al. 1991, Chittenden et al. 1991, Lees et al. 1993, Hiebert 1993, Wu et al. 2001). Once RB1 is phosphorylated on serine residue S795 by Cyclin D:CDK4/6 complexes, it can no longer associate with and inhibit E2F1-3. Thus, CDK4/6-mediated phosphorylation of RB1 leads to transcriptional activation of E2F1-3 target genes needed for the S phase of the cell cycle (Connell-Crowley et al. 1997). CDK2, in complex with cyclin E, contributes to RB1 inactivation and also activates proteins needed for the initiation of DNA replication (Zhang 2007). Expression of D type cyclins is regulated by extracellular mitogens (Cheng et al. 1998, Depoortere et al. 1998). Catalytic activities of CDK4/6 and CDK2 are controlled by CDK inhibitors of the INK4 family (Serrano et al. 1993, Hannon and Beach 1994, Guan et al. 1994, Guan et al. 1996, Parry et al. 1995) and the Cip/Kip family, respectively.

NBN ProteinO60934 (Uniprot-TrEMBL)
Oncogene Induced SenescencePathwayR-HSA-2559585 (Reactome) Oncogene-induced senescence is triggered by high level of RAS/RAF/MAPK signaling that can be caused, for example, by oncogenic mutations in RAS or RAF proteins, or by oncogenic mutations in growth factor receptors, such as EGFR, that act upstream of RAS/RAF/MAPK cascade. Oncogene-induced senescence can also be triggered by high transcriptional activity of E2F1, E2F2 or E2F3 which can be caused, for example, by the loss-of-function of RB1 tumor suppressor.

Oncogenic signals trigger transcription of CDKN2A locus tumor suppressor genes: p16-INK4A and p14-ARF. p16-INK4A and p14-ARF share exons 2 and 3, but are expressed from different promoters and use different reading frames (Quelle et al. 1995). Therefore, while their mRNAs are homologous and are both translationally inhibited by miR-24 microRNA (Lal et al. 2008, To et al. 2012), they share no similarity at the amino acid sequence level and perform distinct functions in the cell. p16-INK4A acts as the inhibitor of cyclin-dependent kinases CDK4 and CDK6 which phosphorylate and inhibit RB1 protein thereby promoting G1 to S transition and cell cycle progression (Serrano et al. 1993). Increased p16-INK4A level leads to hypophosphorylation of RB1, allowing RB1 to inhibit transcription of E2F1, E2F2 and E2F3-target genes that are needed for cell cycle progression, which results in cell cycle arrest in G1 phase. p14-ARF binds and destabilizes MDM2 ubiquitin ligase (Zhang et al. 1998), responsible for ubiquitination and degradation of TP53 (p53) tumor suppressor protein (Wu et al. 1993, Fuchs et al. 1998, Fang et al. 2000). Therefore, increased p14-ARF level leads to increased level of TP53 and increased expression of TP53 target genes, such as p21, which triggers p53-mediated cell cycle arrest and, depending on other factors, may also lead to p53-mediated apoptosis. CDKN2B locus, which encodes an inhibitor of CDK4 and CDK6, p15-INK4B, is located in the vicinity of CDKN2A locus, at the chromosome band 9p21. p15-INK4B, together with p16-INK4A, contributes to senescence of human T-lymphocytes (Erickson et al. 1998) and mouse fibroblasts (Malumbres et al. 2000). SMAD3, activated by TGF-beta-1 signaling, controls senescence in the mouse multistage carcinogenesis model through regulation of MYC and p15-INK4B gene expression (Vijayachandra et al. 2003). TGF-beta-induced p15-INK4B expression is also important for the senescence of hepatocellular carcinoma cell lines (Senturk et al. 2010).

MAP kinases MAPK1 (ERK2) and MAPK3 (ERK1), which are activated by RAS signaling, phosphorylate ETS1 and ETS2 transcription factors in the nucleus (Yang et al. 1996, Seidel et al. 2002, Foulds et al. 2004, Nelson et al. 2010). Phosphorylated ETS1 and ETS2 are able to bind RAS response elements (RREs) in the CDKN2A locus and stimulate p16-INK4A transcription (Ohtani et al. 2004). At the same time, activated ERKs (MAPK1 i.e. ERK2 and MAPK3 i.e. ERK1) phosphorylate ERF, the repressor of ETS2 transcription, which leads to translocation of ERF to the cytosol and increased transcription of ETS2 (Sgouras et al. 1995, Le Gallic et al. 2004). ETS2 can be sequestered and inhibited by binding to ID1, resulting in inhibition of p16-INK4A transcription (Ohtani et al. 2004).

Transcription of p14-ARF is stimulated by binding of E2F transcription factors (E2F1, E2F2 or E2F3) in complex with SP1 to p14-ARF promoter (Parisi et al. 2002).

Oncogenic RAS signaling affects mitochondrial metabolism through an unknown mechanism, leading to increased generation of reactive oxygen species (ROS), which triggers oxidative stress induced senescence pathway. In addition, increased rate of cell division that is one of the consequences of oncogenic signaling, leads to telomere shortening which acts as another senescence trigger.

Oncogenic MAPK signalingPathwayR-HSA-6802957 (Reactome) The importance of the RAS/RAF/MAPK cascade in regulating cellular proliferation, differentiation and survival is highlighted by the fact that components of the pathway are mutated with high frequency in a large number of human cancers. Activating mutations in RAS are found in approximately one third of human cancers, while ~8% of tumors express an activated form of BRAF. RAS pathway activation is also achieved in a smaller subset of cancers by loss-of-function mutations in negative regulators of RAS signaling, such as the RAS GAP NF1(reviewed in Prior et al, 2012; Pylayeva-Gupta et al, 2011; Stephen et al, 2014; Lavoie and Therrien, 2015; Lito et al, 2013; Samatar and Poulikakos, 2014; Maertens and Cichowski, 2014).
Oxidative Stress Induced SenescencePathwayR-HSA-2559580 (Reactome) Oxidative stress, caused by increased concentration of reactive oxygen species (ROS) in the cell, can happen as a consequence of mitochondrial dysfunction induced by the oncogenic RAS (Moiseeva et al. 2009) or independent of oncogenic signaling. Prolonged exposure to interferon-beta (IFNB, IFN-beta) also results in ROS increase (Moiseeva et al. 2006). ROS oxidize thioredoxin (TXN), which causes TXN to dissociate from the N-terminus of MAP3K5 (ASK1), enabling MAP3K5 to become catalytically active (Saitoh et al. 1998). ROS also stimulate expression of Ste20 family kinases MINK1 (MINK) and TNIK through an unknown mechanism, and MINK1 and TNIK positively regulate MAP3K5 activation (Nicke et al. 2005).

MAP3K5 phosphorylates and activates MAP2K3 (MKK3) and MAP2K6 (MKK6) (Ichijo et al. 1997, Takekawa et al. 2005), which act as p38 MAPK kinases, as well as MAP2K4 (SEK1) (Ichijo et al. 1997, Matsuura et al. 2002), which, together with MAP2K7 (MKK7), acts as a JNK kinase.

MKK3 and MKK6 phosphorylate and activate p38 MAPK alpha (MAPK14) and beta (MAPK11) (Raingeaud et al. 1996), enabling p38 MAPKs to phosphorylate and activate MAPKAPK2 (MK2) and MAPKAPK3 (MK3) (Ben-Levy et al. 1995, Clifton et al. 1996, McLaughlin et al. 1996, Sithanandam et al. 1996, Meng et al. 2002, Lukas et al. 2004, White et al. 2007), as well as MAPKAPK5 (PRAK) (New et al. 1998 and 2003, Sun et al. 2007).

Phosphorylation of JNKs (MAPK8, MAPK9 and MAPK10) by MAP3K5-activated MAP2K4 (Deacon and Blank 1997, Fleming et al. 2000) allows JNKs to migrate to the nucleus (Mizukami et al. 1997) where they phosphorylate JUN. Phosphorylated JUN binds FOS phosphorylated by ERK1 or ERK2, downstream of activated RAS (Okazaki and Sagata 1995, Murphy et al. 2002), forming the activated protein 1 (AP-1) complex (FOS:JUN heterodimer) (Glover and Harrison 1995, Ainbinder et al. 1997).

Activation of p38 MAPKs and JNKs downstream of MAP3K5 (ASK1) ultimately converges on transcriptional regulation of CDKN2A locus. In dividing cells, nucleosomes bound to the CDKN2A locus are trimethylated on lysine residue 28 of histone H3 (HIST1H3A) by the Polycomb repressor complex 2 (PRC2), creating the H3K27Me3 (Me3K-28-HIST1H3A) mark (Bracken et al. 2007, Kotake et al. 2007). The expression of Polycomb constituents of PRC2 (Kuzmichev et al. 2002) - EZH2, EED and SUZ12 - and thereby formation of the PRC2, is positively regulated in growing cells by E2F1, E2F2 and E2F3 (Weinmann et al. 2001, Bracken et al. 2003). H3K27Me3 mark serves as a docking site for the Polycomb repressor complex 1 (PRC1) that contains BMI1 (PCGF4) and is therefore named PRC1.4, leading to the repression of transcription of p16-INK4A and p14-ARF from the CDKN2A locus, where PCR1.4 mediated repression of p14-ARF transcription in humans may be context dependent (Voncken et al. 2005, Dietrich et al. 2007, Agherbi et al. 2009, Gao et al. 2012). MAPKAPK2 and MAPKAPK3, activated downstream of the MAP3K5-p38 MAPK cascade, phosphorylate BMI1 of the PRC1.4 complex, leading to dissociation of PRC1.4 complex from the CDKN2A locus and upregulation of p14-ARF transcription (Voncken et al. 2005). AP-1 transcription factor, formed as a result of MAP3K5-JNK signaling, as well as RAS signaling, binds the promoter of KDM6B (JMJD3) gene and stimulates KDM6B expression. KDM6B is a histone demethylase that removes H3K27Me3 mark i.e. demethylates lysine K28 of HIST1H3A, thereby preventing PRC1.4 binding to the CDKN2A locus and allowing transcription of p16-INK4A (Agger et al. 2009, Barradas et al. 2009, Lin et al. 2012).

p16-INK4A inhibits phosphorylation-mediated inactivation of RB family members by CDK4 and CDK6, leading to cell cycle arrest (Serrano et al. 1993). p14-ARF inhibits MDM2-mediated degradation of TP53 (p53) (Zhang et al. 1998), which also contributes to cell cycle arrest in cells undergoing oxidative stress. In addition, phosphorylation of TP53 by MAPKAPK5 (PRAK) activated downstream of MAP3K5-p38 MAPK signaling, activates TP53 and contributes to cellular senescence (Sun et al. 2007).

POT1 ProteinQ9NUX5 (Uniprot-TrEMBL)
POT1ProteinQ9NUX5 (Uniprot-TrEMBL)
RAD50 ProteinQ92878 (Uniprot-TrEMBL)
RB1ProteinP06400 (Uniprot-TrEMBL)
ROS MetaboliteCHEBI:26523 (ChEBI)
SAHFComplexR-HSA-4647600 (Reactome)
Senescence-Associated Secretory Phenotype (SASP)PathwayR-HSA-2559582 (Reactome) The culture medium of senescent cells in enriched in secreted proteins when compared with the culture medium of quiescent i.e. presenescent cells and these secreted proteins constitute the so-called senescence-associated secretory phenotype (SASP), also known as the senescence messaging secretome (SMS). SASP components include inflammatory and immune-modulatory cytokines (e.g. IL6 and IL8), growth factors (e.g. IGFBPs), shed cell surface molecules (e.g. TNF receptors) and survival factors. While the SASP exhibits a wide ranging profile, it is not significantly affected by the type of senescence trigger (oncogenic signalling, oxidative stress or DNA damage) or the cell type (epithelial vs. mesenchymal) (Coppe et al. 2008). However, as both oxidative stress and oncogenic signaling induce DNA damage, the persistent DNA damage may be a deciding SASP initiator (Rodier et al. 2009). SASP components function in an autocrine manner, reinforcing the senescent phenotype (Kuilman et al. 2008, Acosta et al. 2008), and in the paracrine manner, where they may promote epithelial-to-mesenchymal transition (EMT) and malignancy in the nearby premalignant or malignant cells (Coppe et al. 2008). Interleukin-1-alpha (IL1A), a minor SASP component whose transcription is stimulated by the AP-1 (FOS:JUN) complex (Bailly et al. 1996), can cause paracrine senescence through IL1 and inflammasome signaling (Acosta et al. 2013).

Here, transcriptional regulatory processes that mediate the SASP are annotated. DNA damage triggers ATM-mediated activation of TP53, resulting in the increased level of CDKN1A (p21). CDKN1A-mediated inhibition of CDK2 prevents phosphorylation and inactivation of the Cdh1:APC/C complex, allowing it to ubiquitinate and target for degradation EHMT1 and EHMT2 histone methyltransferases. As EHMT1 and EHMT2 methylate and silence the promoters of IL6 and IL8 genes, degradation of these methyltransferases relieves the inhibition of IL6 and IL8 transcription (Takahashi et al. 2012). In addition, oncogenic RAS signaling activates the CEBPB (C/EBP-beta) transcription factor (Nakajima et al. 1993, Lee et al. 2010), which binds promoters of IL6 and IL8 genes and stimulates their transcription (Kuilman et al. 2008, Lee et al. 2010). CEBPB also stimulates the transcription of CDKN2B (p15-INK4B), reinforcing the cell cycle arrest (Kuilman et al. 2008). CEBPB transcription factor has three isoforms, due to three alternative translation start sites. The CEBPB-1 isoform (C/EBP-beta-1) seems to be exclusively involved in growth arrest and senescence, while the CEBPB-2 (C/EBP-beta-2) isoform may promote cellular proliferation (Atwood and Sealy 2010 and 2011). IL6 signaling stimulates the transcription of CEBPB (Niehof et al. 2001), creating a positive feedback loop (Kuilman et al. 2009, Lee et al. 2010). NF-kappa-B transcription factor is also activated in senescence (Chien et al. 2011) through IL1 signaling (Jimi et al. 1996, Hartupee et al. 2008, Orjalo et al. 2009). NF-kappa-B binds IL6 and IL8 promoters and cooperates with CEBPB transcription factor in the induction of IL6 and IL8 transcription (Matsusaka et al. 1993, Acosta et al. 2008). Besides IL6 and IL8, their receptors are also upregulated in senescence (Kuilman et al. 2008, Acosta et al. 2008) and IL6 and IL8 may be master regulators of the SASP.

IGFBP7 is also an SASP component that is upregulated in response to oncogenic RAS-RAF-MAPK signaling and oxidative stress, as its transcription is directly stimulated by the AP-1 (JUN:FOS) transcription factor. IGFBP7 negatively regulates RAS-RAF (BRAF)-MAPK signaling and is important for the establishment of senescence in melanocytes (Wajapeyee et al. 2008).

Please refer to Young and Narita 2009 for a recent review.

Shelterin complexComplexR-HSA-174898 (Reactome)


ComplexR-HSA-5682021 (Reactome)
Shortened telomere:MRN:Ac-K3016-ATM dimer:KAT5ComplexR-HSA-6792710 (Reactome)
Shortened telomere:MRN:KAT5:p-S1981,Ac-K3016-ATMComplexR-HSA-9006829 (Reactome)
Shortened telomere:MRNComplexR-HSA-5682022 (Reactome)
Shortened telomere R-ALL-3785706 (Reactome)
Shortened telomereR-ALL-3785706 (Reactome)
TERF1 ProteinP54274 (Uniprot-TrEMBL)
TERF2 ProteinQ15554 (Uniprot-TrEMBL)
TERF2IP ProteinQ9NYB0 (Uniprot-TrEMBL)
TINF2 ProteinQ9BSI4 (Uniprot-TrEMBL)
TP53 ProteinP04637 (Uniprot-TrEMBL)
TP53 TetramerComplexR-HSA-3209194 (Reactome)
UBN1 ProteinQ9NPG3 (Uniprot-TrEMBL)
UBN1ProteinQ9NPG3 (Uniprot-TrEMBL)
X-ray MetaboliteCHEBI:30212 (ChEBI)
alpha-particle MetaboliteCHEBI:30216 (ChEBI)
beta-particle MetaboliteCHEBI:10545 (ChEBI)
dsDNAR-HSA-5649637 (Reactome)
gamma-ray MetaboliteCHEBI:30212 (ChEBI)
ligated C-strand Okazaki fragment R-ALL-176395 (Reactome)


ComplexR-HSA-3786257 (Reactome)
p-S15-TP53 ProteinP04637 (Uniprot-TrEMBL)
p-S15-TP53 TetramerComplexR-HSA-349474 (Reactome)
p-S1981,Ac-K3016-ATM ProteinQ13315 (Uniprot-TrEMBL)
p-S1981,Ac-K3016-ATMProteinQ13315 (Uniprot-TrEMBL)
proton MetaboliteCHEBI:24636 (ChEBI)

Annotated Interactions

View all...
SourceTargetTypeDatabase referenceComment
ADPArrowR-HSA-5682026 (Reactome)
ADPArrowR-HSA-5693540 (Reactome)
ADPArrowR-HSA-5693609 (Reactome)
ASF1AR-HSA-3878123 (Reactome)
ATM dimer:KAT5R-HSA-5682018 (Reactome)
ATM dimer:KAT5R-HSA-5693612 (Reactome)
ATPR-HSA-5682026 (Reactome)
ATPR-HSA-5693540 (Reactome)
ATPR-HSA-5693609 (Reactome)
Ac-CoAR-HSA-5682044 (Reactome)
Ac-CoAR-HSA-6792712 (Reactome)
ArrowR-HSA-4647594 (Reactome)
CABIN1R-HSA-3878123 (Reactome)
CCNA:CDK2R-HSA-187934 (Reactome)
CCNE:CDK2R-HSA-69562 (Reactome)
CDKN1A geneR-HSA-3786258 (Reactome)
CDKN1A geneR-HSA-4647613 (Reactome)
CDKN1A,CDKN1BR-HSA-187934 (Reactome)
CDKN1A,CDKN1BR-HSA-69562 (Reactome)
CDKN1A,CDKN1Bmim-catalysisR-HSA-69562 (Reactome)
CDKN1AArrowR-HSA-4647613 (Reactome)
CoA-SHArrowR-HSA-5682044 (Reactome)
CoA-SHArrowR-HSA-6792712 (Reactome)


ArrowR-HSA-187934 (Reactome)
Cyclin E:CDK2:CDKN1A,CDKN1BArrowR-HSA-69562 (Reactome)
DNA DSBs:MRN:Ac-K3016-ATM dimer:KAT5ArrowR-HSA-5682044 (Reactome)
DNA DSBs:MRN:Ac-K3016-ATM dimer:KAT5R-HSA-5693540 (Reactome)
DNA DSBs:MRN:Ac-K3016-ATM dimer:KAT5mim-catalysisR-HSA-5693540 (Reactome)
DNA DSBs:MRN:p-S1981,Ac-K3016-ATM:KAT5ArrowR-HSA-5693540 (Reactome)
DNA DSBs:MRN:ATM dimer:KAT5ArrowR-HSA-5693612 (Reactome)
DNA DSBs:MRN:ATM dimer:KAT5R-HSA-5682044 (Reactome)
DNA DSBs:MRN:ATM dimer:KAT5mim-catalysisR-HSA-5682044 (Reactome)
DNA DSBs:MRNArrowR-HSA-3785768 (Reactome)
DNA DSBs:MRNR-HSA-5693612 (Reactome)
DNA double-strand break endsArrowR-HSA-3785704 (Reactome)
DNA double-strand break endsR-HSA-3785768 (Reactome)
DSB inducing agentsR-HSA-3785704 (Reactome)


ArrowR-HSA-4647593 (Reactome)


TBarR-HSA-4647613 (Reactome)
EP400R-HSA-4647593 (Reactome)
Extended And

Processed Telomere End and Associated DNA Binding and Packaging Protein Complex Folded Into Higher Order

R-HSA-3785711 (Reactome)
HIRA:ASF1A:UBN1:CABIN1ArrowR-HSA-3878123 (Reactome)
HIRA:ASF1A:UBN1:CABIN1R-HSA-4647594 (Reactome)
HIRAR-HSA-3878123 (Reactome)
HMGA1R-HSA-4647594 (Reactome)
HMGA2R-HSA-4647594 (Reactome)
Histone H1 bound chromatin DNAR-HSA-4647594 (Reactome)
Histone H1ArrowR-HSA-4647594 (Reactome)
LMNB1TBarR-HSA-4647594 (Reactome)
MRNR-HSA-3785768 (Reactome)
MRNR-HSA-5682020 (Reactome)
POT1ArrowR-HSA-3785711 (Reactome)
R-HSA-187934 (Reactome) During G1, the activity of cyclin-dependent kinases (CDKs) is controlled by the CDK inhibitors (CKIs) CDKN1A (p21) and CDKN1B (p27), thereby preventing premature entry into S phase (Guardavaccaro and Pagano, 2006).
R-HSA-3785704 (Reactome) Reactive oxygen species (ROS) induce DNA double strand breaks (DSBs) (Yu and Anderson 1997) in cells undergoing oxidative stress. In addition to ROS, DSBs can also be directly generated by ionizing radiation. Agents that interfere with the progression of replication forks, such as topoisomerase poisons used in chemotherapy, induce DSBs indirectly (Curtin 2012).
R-HSA-3785711 (Reactome) In somatic cells where telomerase is not active, telomeric DNA shortens with each cell division (Harley et al. 1990, Hastie et al. 1990). This may be especially pronounced in cells undergoing replicative exhaustion due to oncogenic signaling-driven cell division. The shelterin complex, which protects telomeres from being recognized as double strand DNA breaks (reviewed by de Lange 2005), binds telomeric DNA through interaction of its subunits TREF1 (TRF1) and TREF2 (TRF2) with long TTAGGG repeat tracts (Smogorzewska et al. 2000). Telomere shortening due to replicative exhaustion results in a decreased number of TTAGGG repeats, which negatively impacts shelterin binding to telomeric DNA.
R-HSA-3785768 (Reactome) The MRN complex (MRE11A:RAD50:NBN) binds to DNA ends found at double strand breaks (DNA DSBs) (Lee and Paull 2005). In budding yeast, the Mre11:Rad50:Xrs2 complex, homologous to human MRN, rapidly localizes to DNA breaks (Shroff et al. 2004, Lisby et al. 2004).
R-HSA-3786258 (Reactome) TP53 (p53), stabilized by ATM-mediated phosphorylation on S15 (Karlseder et al. 1999) binds CDKN1A (p21) promoter (El-Deiry et al. 1993).
R-HSA-3878123 (Reactome) The evolutionarily conserved complex of HIRA, ASF1A, UBN1 and CABIN1 plays a key role in the formation of senescence-associated heterochromatin foci (SAHF) (Zhang et al. 2005, Banumathy et al. 2009, Rai et al. 2011). Components of this complex, along with other proteins involved in SAHF, accumulate in PML bodies of pre-senescent cells, and relocate to SAHF in senescent cells, with SAHF relocation depending on the functional RB1 and TP53 pathways (Zhang et al. 2005, Ye et al. 2007, Zhang et al. 2007). HIRA serves as a scaffold of HIRA:ASF1A:UBN1:CABIN1 complex, since three different HIRA protein domains interact with ASF1A, UBN1 and CABIN1 (Zhang et al. 2005, Banumathy et al. 2009, Rai et al. 2011). One of the functions of HIRA:ASF1A:UBN1:CABIN1 complex is to deposit histone H3.3 variant onto chromatin, which is dependent on the ASF1A-mediated binding of histone H3, and is involved in the modulation of gene expression in senescent cells (Zhang et al. 2007, Rai et al. 2011).
R-HSA-4647593 (Reactome) EP400 (p400) binds to a CDKN1A promoter region that overlaps with the distal TP53-binding site and can co-localize with TP53 on CDKN1A promoter (Chan et al. 2005).
R-HSA-4647594 (Reactome) Components of the evolutionarily conserved complex of HIRA, ASF1A, UBN1 and CABIN1 accumulate in PML bodies of pre-senescent cells, and relocate to SAHF (senescence-associated heterochromatic foci) in senescent cells, with SAHF relocation depending on the functional RB1 and TP53 pathways (Zhang et al. 2005, Ye et al. 2007, Zhang et al. 2007). The reorganization of heterochromatin into SAHFs is accompanied by reduction in the amount of total and chromatin-bound lamin B1 (LMNB1), and high levels of LMNB1 interfere with SAHF formation (Sadaie et al. 2013). High-mobility group A proteins, HMGA1 and HMGA2, are enriched on chromatin of senescent cells, predominantly localizing to SAHFs, and high HMGA1 and HMGA2 levels, in cooperation with p16-INK4A, promote SAHF formation and repression of E2F target genes in senescent cells. Overexpression of CDK4 and MDM2, which are frequently co-amplified with HMGA2 in cancer cells as a part of 12q13-15 chromosomal band amplification, bypasses HMGA2 and HMGA1 induced cell cycle arrest and SAHF formation (Narita et al. 2006). The accumulation of HMGA proteins on senescent cell chromatin and SAHF formation is accompanied by the loss of the linker histone H1, probably due to a posttranslational mechanism (Funayama et al. 2006). A chromatin remodeling protein EP400 (p400), which is able to bind CDKN1A (p21) promoter and inhibit TP53-mediated activation of CDKN1A transcription, negatively regulates SAHF formation (Chan et al. 2005).
R-HSA-4647613 (Reactome) CDKN1A (p21) is transcriptionally activated by TP53 (p53) after DNA damage (el-Deiry et al. 1993). EP400 (p400) binds to a CDKN1A promoter region that overlaps with the distal TP53-binding site and can co-localize with TP53 on CDKN1A promoter. The presence of EP400 results in the downregulation of CDKN1A transcription without affecting the phosphorylation of TP53 on serine S15 (Chan et al. 2005).
R-HSA-5682018 (Reactome) Activation of ATM kinase in response to shortened telomeres requires association of ATM dimers with the MRN complex bound to DNA ends. MRN subunit RAD50 is essential for ATM dimer binding (Lee and Paull 2005, Wu et al. 2007). Dissociation of the shelterin complex from telomeres activates ATM (Karlseder et al. 1999), consistent with a mutually exclusive binding of shelterin and MRN to telomeric DNA (Wu et al. 2007).
R-HSA-5682020 (Reactome) The MRN complex (MRE11:RAD50:NBS1 also known as MRE11A:RAD50:NBN) binds telomeric DNA, and MRN association with telomeric DNA is mutually exclusive with shelterin binding (Wu et al. 2007).
R-HSA-5682026 (Reactome) MRN bound to shortened telomeres promotes dissociation of ATM dimers to ATM monomers which is accompanied by ATM autophosphorylation on serine residue S1981. Dissociation of ATM dimers requires the ATP-dependent DNA-helicase activity of the MRN subunit RAD50 (Lee and Paull 2005, Wu et al. 2007).
R-HSA-5682044 (Reactome) The histone acetyltransferase Tip60 (KAT5), in addition to forming a histone acetyltransferase complex with NuA4, forms another complex with ATM dimers. The ATM dimer:KAT5 complex is formed in the absence of DNA damage, but the acetyltransferase activity of KAT5 is activated by double strand DNA breaks (DNA DSBs) (Sun et al. 2005). In response to DNA DSBs, the MRN complex targets KAT5 to chromatin, where KAT5 associates with histone H3 trimethylated on lysine 10 (commonly known as H3K9me3 mark). Besides the MRN complex, the ability of KAT5 to access H3K9me3 depends on the DNA damage-induced displacement of HP1beta (CBX1) from H3K9me3 (Ayoub et al. 2008). Binding to H3K9me3 activates the acetyltransferase activity of KAT5 (Sun et al. 2009). KAT5 acetylates ATM on lysine residue K3016 in the highly conserved C-terminal FATC domain of ATM. ATM acetylation is needed for the activation of ATM kinase activity in response to DNA damage (Sun et al. 2007).
R-HSA-5693540 (Reactome) MRN promotes dissociation of ATM dimers to ATM monomers which is accompanied by ATM trans-autophosphorylation on serine residue S1981 (Bakkenist et al. 2003, Du et al. 2014). ATM autophosphorylation at serine residues S367 and S1893 is also implicated in ATM activation (Kozlov et al. 2006). Dissociation of ATM dimers requires the ATP-dependent DNA-helicase activity of the MRN subunit RAD50 (Lee and Paull 2005). KAT5 (Tip60) mediated acetylation of ATM dimers at lysine K3016 is a prerequisite for ATM kinase activity (Sun et al. 2007). Upon the dissociation of ATM dimers induced by DNA double strand breaks (DSBs), a fraction of activated ATM is retained at DSB sites, co-localizing with the MRN complex (Andegeko et al. 2001, Uziel et al. 2003) at ionizing radiation-induced foci (IRIF). MRN facilitates the binding of a portion of ATM substrates to ATM (Lee and Paull 2004).

After the DNA double strand breaks (DSBs) are repaired, ATM is dephosphorylated by an unidentified PP2A phosphatase complex, leading to dimer reformation (Goodarzi et al. 2004).

R-HSA-5693609 (Reactome) In response to DNA double strand breaks, serine at position 15 of the TP53 (p53) tumor suppressor protein is rapidly phosphorylated by the ATM kinase. This serves to stabilize the p53 protein. A rise in the levels of the p53 protein induces the expression of p21 cyclin-dependent kinase inhibitor. This prevents the normal progression from G1 to S phase, thus providing a check on replication of damaged DNA (Banin et al. 1998, Canman et al. 1998, Khanna et al. 1998).
R-HSA-5693612 (Reactome) Activation of ATM kinase in response to DNA damage in the form of DNA double strand breaks (DSBs) requires association of ATM dimers with the MRN complex bound to DNA ends. MRN subunit RAD50 is essential for ATM dimer binding (Lee and Paull 2005, Wu et al. 2007). ATM dimer exists in a preformed complex with KAT5 (Tip60) histone acetyltransferase (Sun et al. 2005).
R-HSA-6792712 (Reactome) The histone acetyltransferase Tip60 (KAT5), in addition to forming a histone acetyltransferase complex with NuA4, forms another complex with ATM dimers. The ATM dimer:KAT5 complex is formed in the absence of DNA damage, but the acetyltransferase activity of KAT5 is activated by double strand DNA breaks (DNA DSBs) (Sun et al. 2005). The activation of KAT5 at shortened telomeres has not been experimentally studied, but KAT5 is assumed to be recruited to shortened telomeres, together with ATM, based on the analogy with ATM activation at DNA DSBs. It is likely that at shortened telomeres, similar to DNA DSBs, the MRN complex targets KAT5 to chromatin, where KAT5 associates with histone H3 trimethylated on lysine 10 (commonly known as H3K9me3 mark). Besides the MRN complex, the ability of KAT5 to access H3K9me3 depends on the DNA damage-induced displacement of HP1beta (CBX1) from H3K9me3 (Ayoub et al. 2008). Similar to DNA DSBs, HP1beta is also displaced from unprotected telomeres (Koering et al. 2002). Binding to H3K9me3 activates the acetyltransferase activity of KAT5 (Sun et al. 2009). KAT5 acetylates ATM on lysine residue K3016 in the highly conserved C-terminal FATC domain of ATM. ATM acetylation is likely needed for the activation of ATM kinase activity at shortened telomeres, as it needed for ATM activation at DNA DSBs (Sun et al. 2007).
R-HSA-69562 (Reactome) During G1, the activity of cyclin-dependent kinases (CDKs) is controlled by the CDK inhibitors (CKIs) CDKN1A (p21) and CDKN1B (p27), thereby preventing premature entry into S phase (see Guardavaccaro and Pagano, 2006). The efficient recognition and ubiquitination of p27 by the SCF (Skp2) complex requires the formation of a trimeric complex containing p27 and cyclin E/A:Cdk2.
SAHFArrowR-HSA-4647594 (Reactome)
Shelterin complexArrowR-HSA-3785711 (Reactome)


ArrowR-HSA-5682018 (Reactome)


R-HSA-6792712 (Reactome)


mim-catalysisR-HSA-6792712 (Reactome)
Shortened telomere:MRN:Ac-K3016-ATM dimer:KAT5ArrowR-HSA-6792712 (Reactome)
Shortened telomere:MRN:Ac-K3016-ATM dimer:KAT5R-HSA-5682026 (Reactome)
Shortened telomere:MRN:Ac-K3016-ATM dimer:KAT5mim-catalysisR-HSA-5682026 (Reactome)
Shortened telomere:MRN:KAT5:p-S1981,Ac-K3016-ATMArrowR-HSA-5682026 (Reactome)
Shortened telomere:MRNArrowR-HSA-5682020 (Reactome)
Shortened telomere:MRNR-HSA-5682018 (Reactome)
Shortened telomereArrowR-HSA-3785711 (Reactome)
Shortened telomereR-HSA-5682020 (Reactome)
TBarR-HSA-4647594 (Reactome)
TP53 TetramerR-HSA-5693609 (Reactome)
UBN1R-HSA-3878123 (Reactome)
dsDNAR-HSA-3785704 (Reactome)


ArrowR-HSA-3786258 (Reactome)


ArrowR-HSA-4647613 (Reactome)


R-HSA-4647593 (Reactome)
p-S15-TP53 TetramerArrowR-HSA-4647594 (Reactome)
p-S15-TP53 TetramerArrowR-HSA-5693609 (Reactome)
p-S15-TP53 TetramerR-HSA-3786258 (Reactome)
p-S1981,Ac-K3016-ATMArrowR-HSA-5682026 (Reactome)
p-S1981,Ac-K3016-ATMArrowR-HSA-5693540 (Reactome)
p-S1981,Ac-K3016-ATMmim-catalysisR-HSA-5693609 (Reactome)

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