miRNA regulation of DNA damage response (WP1530)

Homo sapiens

This is the first of two pathways which deals with the DNA damage response. It comprises two central gene products (ATM and ATR) influenced by different sources of DNA damage (in blue). The two central genes can both be divides into their most important genes. For the ATM pathway these are TP53 and CHEK2, while CHEK1 is most important for the ATR pathway. The goal of this first pathway is to provide an overview of the most important gene products, processes and changes in cell condition elicited by the DNA damage response while keeping it clear and understandable. Also some microRNAs are implemented to visualize the possible effects they can induce. By doing so a better understanding of the role microRNA play in the DNA damage response might arise. All processes take place in the cytoplasm, except when mentioned differently. Proteins on this pathway have targeted assays available via the [https://assays.cancer.gov/available_assays?wp_id=WP1530 CPTAC Assay Portal].


Jan Krumeich , Stan Gaj , Martina Summer-Kutmon , Andra Waagmeester , Martijn Van Iersel , Kristina Hanspers , Egon Willighagen , Alex Pico , Zahra Roudbari , Ryan Miller , Susan Coort , Finterly Hu , Eric Weitz , and Vanessa Sousa


last edited

Discuss this pathway

Check for ongoing discussions or start your own.

Cited In

Are you planning to include this pathway in your next publication? See How to Cite and add a link here to your paper once it's online.


Homo sapiens




Pathway Ontology

microRNA pathway DNA repair pathway


Label Type Compact URI Comment
Alkylating agents Metabolite chebi:22333
Estradiol Metabolite chebi:16469
Caffeine Metabolite chemspider:2424
7-hydroxystaurosporine Metabolite chemspider:65225
RAD51 GeneProduct ensembl:ENSG00000051180
APAF1 GeneProduct ensembl:ENSG00000120868
CCNB2 GeneProduct ensembl:ENSG00000157456
RAD52 GeneProduct ensembl:ENSG00000002016
RB1 GeneProduct ensembl:ENSG00000139687
GADD45B GeneProduct ensembl:ENSG00000099860
CDKN1A GeneProduct ensembl:ENSG00000124762
ABL1 GeneProduct ensembl:ENSG00000097007
ATR GeneProduct ensembl:ENSG00000175054
CDK2 GeneProduct ensembl:ENSG00000123374
CCND3 GeneProduct ensembl:ENSG00000112576
GADD45A GeneProduct ensembl:ENSG00000116717
CDKN1B GeneProduct ensembl:ENSG00000111276
RAD17 GeneProduct ensembl:ENSG00000152942
RFC GeneProduct ncbigene:5981
CHEK1 GeneProduct ensembl:ENSG00000149554
PIDD GeneProduct ncbigene:55367
TP53AIP1 GeneProduct ensembl:ENSG00000120471
CCND1 GeneProduct ensembl:ENSG00000110092
BID GeneProduct ensembl:ENSG00000015475
CASP9 GeneProduct ensembl:ENSG00000132906
GADD45G GeneProduct ensembl:ENSG00000130222
CCND2 GeneProduct ensembl:ENSG00000118971
PML GeneProduct ensembl:ENSG00000140464
NBN GeneProduct ncbigene:4683
CHEK2 GeneProduct ensembl:ENSG00000183765
FANCD2 GeneProduct ensembl:ENSG00000144554
CDK5 GeneProduct ensembl:ENSG00000164885
TLK2 GeneProduct ensembl:ENSG00000146872
TLK1 GeneProduct ensembl:ENSG00000198586
GADD45G GeneProduct ensembl:ENSG00000130222
SFN GeneProduct ensembl:ENSG00000175793
MIR15A GeneProduct ensembl:ENSG00000283785
BRCA1 GeneProduct ensembl:ENSG00000012048
GADD45B GeneProduct ensembl:ENSG00000099860
DDB2 GeneProduct ensembl:ENSG00000134574
PMAIP1 GeneProduct ensembl:ENSG00000141682
RB1 GeneProduct ensembl:ENSG00000139687
RPA2 GeneProduct ensembl:ENSG00000117748
GADD45A GeneProduct ensembl:ENSG00000116717
MDM2 GeneProduct ensembl:ENSG00000135679
FAS GeneProduct ensembl:ENSG00000026103
CCNE2 GeneProduct ensembl:ENSG00000175305
RAD1 GeneProduct ensembl:ENSG00000113456
PRKDC GeneProduct ensembl:ENSG00000253729
CASP8 GeneProduct ensembl:ENSG00000064012
CCNG1 GeneProduct ensembl:ENSG00000113328
BAX GeneProduct ensembl:ENSG00000087088
CASP3 GeneProduct ensembl:ENSG00000164305
CDK6 GeneProduct ensembl:ENSG00000105810
ATM GeneProduct ensembl:ENSG00000149311
SESN1 GeneProduct ensembl:ENSG00000080546
E2F1 GeneProduct ensembl:ENSG00000101412
CDK4 GeneProduct ensembl:ENSG00000135446
SMC1A GeneProduct ensembl:ENSG00000072501
CYCS GeneProduct ensembl:ENSG00000172115
MIR20A GeneProduct ensembl:ENSG00000283762
TP53 GeneProduct ensembl:ENSG00000141510
MIR145 GeneProduct ensembl:ENSG00000276365
HUS1 GeneProduct ensembl:ENSG00000188996
CCNE1 GeneProduct ensembl:ENSG00000105173
CCNB3 GeneProduct ensembl:ENSG00000147082
BBC3 GeneProduct ensembl:ENSG00000105327
RAD50 GeneProduct ensembl:ENSG00000113522
c-Myc GeneProduct ncbigene:4609
E2F1 GeneProduct ensembl:ENSG00000101412
RRM2B GeneProduct ensembl:ENSG00000048392
CDK1 GeneProduct ensembl:ENSG00000170312
CREB1 GeneProduct ncbigene:1385
MRE11 GeneProduct ncbigene:4361
CDC25C GeneProduct ensembl:ENSG00000158402
ATRIP GeneProduct ncbigene:84126
RAD9A GeneProduct ensembl:ENSG00000172613
TNFRSF10B GeneProduct ensembl:ENSG00000120889
H2AFX GeneProduct ensembl:ENSG00000188486
hsa-mir-24-1 GeneProduct ensembl:ENSG00000284459
CCNB1 GeneProduct ensembl:ENSG00000134057
CDC25A GeneProduct ensembl:ENSG00000164045


  1. The Bcl-2 family: roles in cell survival and oncogenesis. Cory S, Huang DCS, Adams JM. Oncogene. 2003 Nov 24;22(53):8590–607. PubMed Europe PMC Scholia
  2. Dynamics of the p53-Mdm2 feedback loop in individual cells. Lahav G, Rosenfeld N, Sigal A, Geva-Zatorsky N, Levine AJ, Elowitz MB, et al. Nat Genet. 2004 Feb;36(2):147–50. PubMed Europe PMC Scholia
  3. Targeting the checkpoint kinases: chemosensitization versus chemoprotection. Zhou BBS, Bartek J. Nat Rev Cancer. 2004 Mar;4(3):216–25. PubMed Europe PMC Scholia
  4. The negative role of cyclin G in ATM-dependent p53 activation. Ohtsuka T, Jensen MR, Kim HG, Kim KT, Lee SW. Oncogene. 2004 Jul 8;23(31):5405–8. PubMed Europe PMC Scholia
  5. Wagging the dogma; tissue-specific cell cycle control in the mouse embryo. Pagano M, Jackson PK. Cell. 2004 Sep 3;118(5):535–8. PubMed Europe PMC Scholia
  6. Transcription - guarding the genome by sensing DNA damage. Ljungman M, Lane DP. Nat Rev Cancer. 2004 Sep;4(9):727–37. PubMed Europe PMC Scholia
  7. Living with or without cyclins and cyclin-dependent kinases. Sherr CJ, Roberts JM. Genes Dev. 2004 Nov 15;18(22):2699–711. PubMed Europe PMC Scholia
  8. Chromosomal instability in oral cancer cells. Reshmi SC, Gollin SM. J Dent Res. 2005 Feb;84(2):107–17. PubMed Europe PMC Scholia
  9. p53: traffic cop at the crossroads of DNA repair and recombination. Sengupta S, Harris CC. Nat Rev Mol Cell Biol. 2005 Jan;6(1):44–55. PubMed Europe PMC Scholia
  10. The role of BH3-only proteins in the immune system. Strasser A. Nat Rev Immunol. 2005 Mar;5(3):189–200. PubMed Europe PMC Scholia
  11. c-Myc-regulated microRNAs modulate E2F1 expression. O’Donnell KA, Wentzel EA, Zeller KI, Dang CV, Mendell JT. Nature. 2005 Jun 9;435(7043):839–43. PubMed Europe PMC Scholia
  12. Surviving the breakup: the DNA damage checkpoint. Harrison JC, Haber JE. Annu Rev Genet. 2006;40:209–35. PubMed Europe PMC Scholia
  13. Regulation of the INK4b-ARF-INK4a tumour suppressor locus: all for one or one for all. Gil J, Peters G. Nat Rev Mol Cell Biol. 2006 Sep;7(9):667–77. PubMed Europe PMC Scholia
  14. Polycomb silencers control cell fate, development and cancer. Sparmann A, van Lohuizen M. Nat Rev Cancer. 2006 Nov;6(11):846–56. PubMed Europe PMC Scholia
  15. Regulating the p53 pathway: in vitro hypotheses, in vivo veritas. Toledo F, Wahl GM. Nat Rev Cancer. 2006 Dec;6(12):909–23. PubMed Europe PMC Scholia
  16. An E2F/miR-20a autoregulatory feedback loop. Sylvestre Y, De Guire V, Querido E, Mukhopadhyay UK, Bourdeau V, Major F, et al. J Biol Chem. 2007 Jan 26;282(4):2135–43. PubMed Europe PMC Scholia
  17. Direct regulation of an oncogenic micro-RNA cluster by E2F transcription factors. Woods K, Thomson JM, Hammond SM. J Biol Chem. 2007 Jan 26;282(4):2130–4. PubMed Europe PMC Scholia
  18. p53 in health and disease. Vousden KH, Lane DP. Nat Rev Mol Cell Biol. 2007 Apr;8(4):275–83. PubMed Europe PMC Scholia
  19. CDC25 phosphatases in cancer cells: key players? Good targets? Boutros R, Lobjois V, Ducommun B. Nat Rev Cancer. 2007 Jul;7(7):495–507. PubMed Europe PMC Scholia
  20. miR-221 and miR-222 expression affects the proliferation potential of human prostate carcinoma cell lines by targeting p27Kip1. Galardi S, Mercatelli N, Giorda E, Massalini S, Frajese GV, Ciafrè SA, et al. J Biol Chem. 2007 Aug 10;282(32):23716–24. PubMed Europe PMC Scholia
  21. Emergence of a DNA-damage response network consisting of Fanconi anaemia and BRCA proteins. Wang W. Nat Rev Genet. 2007 Oct;8(10):735–48. PubMed Europe PMC Scholia
  22. The impact of a negligent G2/M checkpoint on genomic instability and cancer induction. Löbrich M, Jeggo PA. Nat Rev Cancer. 2007 Nov;7(11):861–9. PubMed Europe PMC Scholia
  23. CHK2 kinase: cancer susceptibility and cancer therapy - two sides of the same coin? Antoni L, Sodha N, Collins I, Garrett MD. Nat Rev Cancer. 2007 Dec;7(12):925–36. PubMed Europe PMC Scholia
  24. MicroRNAs in the miR-106b family regulate p21/CDKN1A and promote cell cycle progression. Ivanovska I, Ball AS, Diaz RL, Magnus JF, Kibukawa M, Schelter JM, et al. Mol Cell Biol. 2008 Apr;28(7):2167–74. PubMed Europe PMC Scholia
  25. MiR-221 controls CDKN1C/p57 and CDKN1B/p27 expression in human hepatocellular carcinoma. Fornari F, Gramantieri L, Ferracin M, Veronese A, Sabbioni S, Calin GA, et al. Oncogene. 2008 Sep 25;27(43):5651–61. PubMed Europe PMC Scholia
  26. Genetic and epigenetic silencing of microRNA-203 enhances ABL1 and BCR-ABL1 oncogene expression. Bueno MJ, Pérez de Castro I, Gómez de Cedrón M, Santos J, Calin GA, Cigudosa JC, et al. Cancer Cell. 2008 Jun;13(6):496–506. PubMed Europe PMC Scholia
  27. miR-16 family induces cell cycle arrest by regulating multiple cell cycle genes. Liu Q, Fu H, Sun F, Zhang H, Tie Y, Zhu J, et al. Nucleic Acids Res. 2008 Sep;36(16):5391–404. PubMed Europe PMC Scholia
  28. MicroRNA15a modulates expression of the cell-cycle regulator Cdc25A and affects hepatic cystogenesis in a rat model of polycystic kidney disease. Lee SO, Masyuk T, Splinter P, Banales JM, Masyuk A, Stroope A, et al. J Clin Invest. 2008 Nov;118(11):3714–24. PubMed Europe PMC Scholia
  29. p53-Repressed miRNAs are involved with E2F in a feed-forward loop promoting proliferation. Brosh R, Shalgi R, Liran A, Landan G, Korotayev K, Nguyen GH, et al. Mol Syst Biol. 2008;4:229. PubMed Europe PMC Scholia
  30. Concurrent hormone and radiation therapy in patients with breast cancer: what is the rationale? Chargari C, Toillon RA, Macdermed D, Castadot P, Magné N. Lancet Oncol. 2009 Jan;10(1):53–60. PubMed Europe PMC Scholia
  31. MicroRNA involvement in hepatocellular carcinoma. Gramantieri L, Fornari F, Callegari E, Sabbioni S, Lanza G, Croce CM, et al. J Cell Mol Med. 2008 Dec;12(6A):2189–204. PubMed Europe PMC Scholia
  32. MicroRNA regulation of DNA repair gene expression in hypoxic stress. Crosby ME, Kulshreshtha R, Ivan M, Glazer PM. Cancer Res. 2009 Feb 1;69(3):1221–9. PubMed Europe PMC Scholia
  33. p53 represses c-Myc through induction of the tumor suppressor miR-145. Sachdeva M, Zhu S, Wu F, Wu H, Walia V, Kumar S, et al. Proc Natl Acad Sci U S A. 2009 Mar 3;106(9):3207–12. PubMed Europe PMC Scholia
  34. miR-34b targets cyclic AMP-responsive element binding protein in acute myeloid leukemia. Pigazzi M, Manara E, Baron E, Basso G. Cancer Res. 2009 Mar 15;69(6):2471–8. PubMed Europe PMC Scholia
  35. miR-181a regulates cap-dependent translation of p27(kip1) mRNA in myeloid cells. Cuesta R, Martínez-Sánchez A, Gebauer F. Mol Cell Biol. 2009 May;29(10):2841–51. PubMed Europe PMC Scholia
  36. miR-24-mediated downregulation of H2AX suppresses DNA repair in terminally differentiated blood cells. Lal A, Pan Y, Navarro F, Dykxhoorn DM, Moreau L, Meire E, et al. Nat Struct Mol Biol. 2009 May;16(5):492–8. PubMed Europe PMC Scholia
  37. MicroRNA-mediated gene silencing modulates the UV-induced DNA-damage response. Pothof J, Verkaik NS, van IJcken W, Wiemer EAC, Ta VTB, van der Horst GTJ, et al. EMBO J. 2009 Jul 22;28(14):2090–9. PubMed Europe PMC Scholia
  38. MicroRNA-330 acts as tumor suppressor and induces apoptosis of prostate cancer cells through E2F1-mediated suppression of Akt phosphorylation. Lee KH, Chen YL, Yeh SD, Hsiao M, Lin JT, Goan YG, et al. Oncogene. 2009 Sep 24;28(38):3360–70. PubMed Europe PMC Scholia
  39. microRNA-21 negatively regulates Cdc25A and cell cycle progression in colon cancer cells. Wang P, Zou F, Zhang X, Li H, Dulak A, Tomko RJ Jr, et al. Cancer Res. 2009 Oct 15;69(20):8157–65. PubMed Europe PMC Scholia
  40. miR-449a and miR-449b are direct transcriptional targets of E2F1 and negatively regulate pRb-E2F1 activity through a feedback loop by targeting CDK6 and CDC25A. Yang X, Feng M, Jiang X, Wu Z, Li Z, Aau M, et al. Genes Dev. 2009 Oct 15;23(20):2388–93. PubMed Europe PMC Scholia
  41. Cell-cycle regulator E2F1 and microRNA-223 comprise an autoregulatory negative feedback loop in acute myeloid leukemia. Pulikkan JA, Dengler V, Peramangalam PS, Peer Zada AA, Müller-Tidow C, Bohlander SK, et al. Blood. 2010 Mar 4;115(9):1768–78. PubMed Europe PMC Scholia
  42. ATM is down-regulated by N-Myc-regulated microRNA-421. Hu H, Du L, Nagabayashi G, Seeger RC, Gatti RA. Proc Natl Acad Sci U S A. 2010 Jan 26;107(4):1506–11. PubMed Europe PMC Scholia
  43. microRNA expression profile and identification of miR-29 as a prognostic marker and pathogenetic factor by targeting CDK6 in mantle cell lymphoma. Zhao JJ, Lin J, Lwin T, Yang H, Guo J, Kong W, et al. Blood. 2010 Apr 1;115(13):2630–9. PubMed Europe PMC Scholia
  44. The miR-17-92 microRNA polycistron regulates MLL leukemia stem cell potential by modulating p21 expression. Wong P, Iwasaki M, Somervaille TCP, Ficara F, Carico C, Arnold C, et al. Cancer Res. 2010 May 1;70(9):3833–42. PubMed Europe PMC Scholia
  45. p53/microRNA-374b/AKT1 regulates colorectal cancer cell apoptosis in response to DNA damage. Gong H, Cao Y, Han G, Zhang Y, You Q, Wang Y, et al. Int J Oncol. 2017 May;50(5):1785–91. PubMed Europe PMC Scholia