Fanconi Anemia Pathway (Homo sapiens)

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4, 6, 11, 17, 20...1, 2, 8, 10, 14...31, 42397, 22, 24, 3611, 19, 53, 5422, 3718, 26, 28, 43, 44, 49...9, 16, 31, 34, 42...10, 14, 23, 27, 29...18, 25, 28, 33, 43...541, 4622, 24, 36, 37, 47nucleoplasmcytosolp-T691,S717-FANCD2 UBA52(1-76) UBB(153-228) UBC(609-684) UBC(305-380) FANCF FANCA FAAP100 SLX1A MonoUb:K561,p-T691,S717-FANCD2:MonoUb:K523,p-4S-FANCI:FA Core Complex:ICL-DNA:Unhooking nucleasesFANCC FANCM FANCA APITD1 FANCG ICL-DNA UBC(609-684) FANCB FANCE ATPFANCF FANCD2:FANCI:UBE2T:FA Core Complex:ICL-DNAADPUBB(153-228) UBA52(1-76) FANCA FANCG FANCA FAAP24 UBC(609-684) FANCI FANCE UBC(305-380) FANCM FANCB FANCC UBC(77-152) UBC(305-380) FANCE RPA1 FANCL FANCC FANCD2 FANCF FANCAFANCLUBC(457-532) FAAP100 FANCL FANCC ATR FANCL UBB(153-228) UBC(1-76) STRA13 FANCM UBC(77-152) Nucleotide ExcisionRepairUBC(77-152) p-4S-FANCI UBC(153-228) MonoUb:K561,p-T691,S717-FANCD2:MonoUb:K523,p-4S-FANCI:FA Core Complex:Unhooked ICL-DNA:POLNICL-DNA WDR48 FANCI MUS81 UBC(229-304) FANCM:FAAP24:APITD1:STRA13:ICL-DNARPA1 FANCL PPiFAAP20 RPA3 FANCC UBC(77-152) UBC(533-608) FANCL MUS81 UBC(229-304) FANCE DCLRE1A p-T691,S717-FANCD2 FAAP24 UBB(153-228) APITD1 MonoUb-K561,p-T691,S717-FANCD2 MonoUb:K561,p-T691,S717-FANCD2:MonoUb:K523,p-4S-FANCIFANCMFAAP100 p-FANCD2:p-FANCI:UBE2T:p-FA Core Complex:ICL-DNAFANCF RPS27A(1-76) UBC(457-532) FANCGFANCG p-S1045-FANCM FAAP100 FANCM FANCC FANCA FAAP24 FANCG UBC(229-304) APITD1 FANCA p-4S-FANCI FANCF ICL-DNA p-FANCD2:p-FANCIFAAP20 EME1 FAAP24 APITD1 FANCC FANCF MonoUb-K561,p-T691,S717-FANCD2 UBB(1-76) APITD1 MonoUb-K523,p-4S-FANCI UBB(153-228) UBB(1-76) UBB(1-76) MonoUb-K561,p-T691,S717-FANCD2 p-S1045-FANCM FANCB RPS27A(1-76) UBB(1-76) FAAP20 FANCB FANCL UBB(77-152) FANCB p-S1045-FANCM UBB(77-152) ATRIP ICL-DNA UBC(77-152) FAAP100 FAAP20 FAAP24 APITD1 MonoUb:K91,K182-UBE2TFANCM FANCA UBC(609-684) UBB(153-228) UBB(77-152) UBB(1-76) UBC(305-380) UBC(533-608) APITD1 FAAP100 DNA Double-StrandBreak RepairUBC(1-76) FANCD2 FANCM FANCL MonoUb:K561,p-T691,S717-FANCD2:MonoUb:K523,p-4S-FANCI:FA Core Complex:ICL-DNAUBC(381-456) FAAP24 UBC(381-456) FANCL FAAP20FANCB UBA52(1-76) MonoUb-K523,p-4S-FANCI UBC(381-456) UBC(457-532) STRA13 UBC(153-228) UBA52(1-76) FA CoreComplex:ICL-DNAFANCB UBC(533-608) RPS27A(1-76) ATR UBC(609-684) APITD1:STRA13octamerUBC(229-304) UBC(533-608) p-S1045-FANCM APITD1 FAAP100FANCFUBC(77-152) FANCE UBC(457-532) FAAP100 UBB(153-228) UBC(457-532) FANCD2:FANCIFAAP20 FANCB UBC(1-76) FAAP24 FANCG FANCIFAAP100 DCLRE1B ATRIP FANCE FANCC STRA13 DCLRE1A RPA3 FANCA UBC(305-380) RPA3 FANCF ERCC4 MonoUb-K523,p-4S-FANCI UBE2T FANCI FAAP20 ERCC1 RPA2 UBC(457-532) UBC(533-608) Unhooked ICL-DNA STRA13 FANCF FAAP24 UBC(153-228) USP1:WDR48RPS27A(1-76) DNA double-strandbreak endsSLX4 SLX4 STRA13 APITD1 ERCC4 EME1 UBC(153-228) UBE2TFANCM:FAAP24FANCF FANCM POLNUBC(305-380) RPS27A(1-76) FANCCUBC(1-76) FAAP24 UBA52(1-76) FANCE FANCG UBC(305-380) ICL-DNA UBC(229-304) POLN UbSTRA13 UBC(1-76) ICL-DNA ICL-DNA FAN1FANCD2RPA1 STRA13 RPA heterotrimerUBC(381-456) UBC(229-304) FANCB RPS27A(1-76) FANCE FANCL EME2 p-RPA heterotrimerMonoUb:K561,p-T691,S717-FANCD2:MonoUb:K523,p-4S-FANCI:FA Core Complex:Unhooked ICL-DNAFAAP24FANCL FANCB MonoUb-K523,p-4S-FANCI UBC(1-76) FANCD2:FANCI:UBE2T:FA Core Complex:ICL-DNA:RPA:ATR:ATRIPFANCG STRA13 Unhooked ICL-DNA UBB(77-152) p-S1045-FANCM STRA13 UBB(1-76) UBA52(1-76) FANCF FAAP100 FAAP24 FANCE STRA13 FAAP20 FAAP20 FANCE FANCC UBC(381-456) FANCG EME2 UBB(77-152) UBE2T UBC(381-456) FAAP24 UBB(77-152) ERCC1 ICL-DNAUBC(381-456) ICL-DNA FANCBSLX1A:SLX4:MUS81:EME1,(MUS81:EME2)FANCERPA2 UBB(77-152) FAAP24 UBC(533-608) MonoUb-K561,p-T691,S717-FANCD2 FANCG UBC(457-532) FAAP20 ATR:ATRIPMonoUb-K91,K182-UBE2T MonoUb-K523,p-4S-FANCI p-S33-RPA2 UBC(609-684) UBC(153-228) FANCC ERCC1:ERCC4APITD1 FAAP20 FANCG UBE2T UBB(1-76) UBC(229-304) DCLRE1B FANCD2 p-FA Core ComplexMonoUb-K561,p-T691,S717-FANCD2 dNTPUBC(153-228) FANCA SLX1A USP1 UBC(533-608) UBC(1-76) FAN1 UBC(153-228) UBA52(1-76) FANCA DCLRE1A,DCLRE1BDistorted dsDNARPS27A(1-76) UBC(77-152) UBC(609-684) p-FA CoreComplex:ICL-DNAFAAP100 5, 12, 13, 21, 50...393, 4033, 5235, 45


Fanconi anemia (FA) is a genetic disease of genome instability characterized by congenital skeletal defects, aplastic anemia, susceptibility to leukemias, and cellular sensitivity to DNA damaging agents. Patients with FA have been categorized into at least 15 complementation groups (FA-A, -B, -C, -D1, -D2, -E, -F, -G, -I, -J, -L, -M, -N, -O and -P). These complementation groups correspond to the genes FANCA, FANCB, FANCC, FANCD1/BRCA2, FANCD2, FANCE, FANCF, FANCG, FANCJ/BRIP1, FANCL, FANCM, FANCN/PALB2, FANCO/RAD51C and FANCP/SLX4. Eight of these proteins, FANCA, FANCB, FANCC, FANCE, FANCF, FANCG, FANCL, and FANCM, together with FAAP24, FAAP100, FAAP20, APITD1 and STRA13, form a nuclear complex termed the FA core complex. The FA core complex is an E3 ubiquitin ligase that recognizes and is activated by DNA damage in the form of interstrand crosslinks (ICLs), triggering monoubiquitination of FANCD2 and FANCI, which initiates repair of ICL-DNA.

FANCD2 and FANCI form a complex and are mutually dependent on one another for their respective monoubiquitination. After DNA damage and during S phase, FANCD2 localizes to discrete nuclear foci that colocalize with proteins involved in homologous recombination repair, such as BRCA1 and RAD51. The FA pathway is regulated by ubiquitination and phosphorylation of FANCD2 and FANCI. ATR-dependent phosphorylation of FANCI and FANCD2 promotes monoubiquitination of FANCD2, stimulating the FA pathway (Cohn and D'Andrea 2008, Wang 2007). The complex of USP1 and WDR48 (UAF1) is responsible for deubiquitination of FANCD2 and negatively regulates the FA pathway (Cohn et al. 2007). <p>Monoubiquitinated FANCD2 recruits DNA nucleases, including SLX4 (FANCP) and FAN1, which unhook the ICL from one of the two covalently linked DNA strands. The DNA polymerase nu (POLN) performs translesion DNA synthesis using the DNA strand with unhooked ICL as a template, thereby bypassing the unhooked ICL. The unhooked ICL is subsequently removed from the DNA via nucleotide excision repair (NER). Incision of the stalled replication fork during the unhooking step generates a double strand break (DSB). The DSB is repaired via homologous recombination repair (HRR) and involves the FA genes BRCA2 (FANCD1), PALB2 (FANCN) and BRIP1 (FANCJ) (reviewed by Deans and West 2011, Kottemann and Smogorzewska 2013). Homozygous mutations in BRCA2, PALB2 or BRIP1 result in Fanconi anemia, while heterozygous mutations in these genes predispose carriers to primarily breast and ovarian cancer. Well established functions of BRCA2, PALB2 and BRIP1 in DNA repair are BRCA1 dependent, but it is not yet clear whether there are additional roles for these proteins in the Fanconi anemia pathway that do not rely on BRCA1 (Evans and Longo 2014, Jiang and Greenberg 2015). Heterozygous BRCA1 mutations predispose carriers to breast and ovarian cancer with high penetrance. Complete loss of BRCA1 function is embryonic lethal. It has only recently been reported that a partial germline loss of BRCA1 function via mutations that diminish protein binding ability of the BRCT domain of BRCA1 result in a FA-like syndrome. BRCA1 has therefore been designated as the FANCS gene (Jiang and Greenberg 2015).<p>The FA pathway is involved in repairing DNA ICLs that arise by exposure to endogenous mutagens produced as by-products of normal cellular metabolism, such as aldehyde containing compounds. Disruption of the aldehyde dehydrogenase gene ALDH2 in FANCD2 deficient mice leads to severe developmental defects, early lethality and predisposition to leukemia. In addition to this, the double knockout mice are exceptionally sensitive to ethanol consumption, as ethanol metabolism results in accumulated levels of aldehydes (Langevin et al. 2011). View original pathway at:Reactome.</div>


Pathway is converted from Reactome ID: 6783310
Reactome version: 66
Reactome Author 
Reactome Author: Matthews, Lisa

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  1. Joo W, Xu G, Persky NS, Smogorzewska A, Rudge DG, Buzovetsky O, Elledge SJ, Pavletich NP.; ''Structure of the FANCI-FANCD2 complex: insights into the Fanconi anemia DNA repair pathway.''; PubMed
  2. Sims AE, Spiteri E, Sims RJ, Arita AG, Lach FP, Landers T, Wurm M, Freund M, Neveling K, Hanenberg H, Auerbach AD, Huang TT.; ''FANCI is a second monoubiquitinated member of the Fanconi anemia pathway.''; PubMed
  3. Ball HL, Cortez D.; ''ATRIP oligomerization is required for ATR-dependent checkpoint signaling.''; PubMed
  4. Evans MK, Longo DL.; ''PALB2 mutations and breast-cancer risk.''; PubMed
  5. Lindahl T, Wood RD.; ''Quality control by DNA repair.''; PubMed
  6. Langevin F, Crossan GP, Rosado IV, Arends MJ, Patel KJ.; ''Fancd2 counteracts the toxic effects of naturally produced aldehydes in mice.''; PubMed
  7. Leung JW, Wang Y, Fong KW, Huen MS, Li L, Chen J.; ''Fanconi anemia (FA) binding protein FAAP20 stabilizes FA complementation group A (FANCA) and participates in interstrand cross-link repair.''; PubMed
  8. Alpi AF, Pace PE, Babu MM, Patel KJ.; ''Mechanistic insight into site-restricted monoubiquitination of FANCD2 by Ube2t, FANCL, and FANCI.''; PubMed
  9. Shigechi T, Tomida J, Sato K, Kobayashi M, Eykelenboom JK, Pessina F, Zhang Y, Uchida E, Ishiai M, Lowndes NF, Yamamoto K, Kurumizaka H, Maehara Y, Takata M.; ''ATR-ATRIP kinase complex triggers activation of the Fanconi anemia DNA repair pathway.''; PubMed
  10. Rajendra E, Oestergaard VH, Langevin F, Wang M, Dornan GL, Patel KJ, Passmore LA.; ''The genetic and biochemical basis of FANCD2 monoubiquitination.''; PubMed
  11. Deans AJ, West SC.; ''DNA interstrand crosslink repair and cancer.''; PubMed
  12. Christmann M, Tomicic MT, Roos WP, Kaina B.; ''Mechanisms of human DNA repair: an update.''; PubMed
  13. Hanawalt PC, Spivak G.; ''Transcription-coupled DNA repair: two decades of progress and surprises.''; PubMed
  14. Longerich S, Kwon Y, Tsai MS, Hlaing AS, Kupfer GM, Sung P.; ''Regulation of FANCD2 and FANCI monoubiquitination by their interaction and by DNA.''; PubMed
  15. Smogorzewska A, Matsuoka S, Vinciguerra P, McDonald ER, Hurov KE, Luo J, Ballif BA, Gygi SP, Hofmann K, D'Andrea AD, Elledge SJ.; ''Identification of the FANCI protein, a monoubiquitinated FANCD2 paralog required for DNA repair.''; PubMed
  16. Singh TR, Ali AM, Paramasivam M, Pradhan A, Wahengbam K, Seidman MM, Meetei AR.; ''ATR-dependent phosphorylation of FANCM at serine 1045 is essential for FANCM functions.''; PubMed
  17. Cohn MA, D'Andrea AD.; ''Chromatin recruitment of DNA repair proteins: lessons from the fanconi anemia and double-strand break repair pathways.''; PubMed
  18. Kratz K, Schöpf B, Kaden S, Sendoel A, Eberhard R, Lademann C, Cannavó E, Sartori AA, Hengartner MO, Jiricny J.; ''Deficiency of FANCD2-associated nuclease KIAA1018/FAN1 sensitizes cells to interstrand crosslinking agents.''; PubMed
  19. Yamanaka K, Minko IG, Takata K, Kolbanovskiy A, Kozekov ID, Wood RD, Rizzo CJ, Lloyd RS.; ''Novel enzymatic function of DNA polymerase nu in translesion DNA synthesis past major groove DNA-peptide and DNA-DNA cross-links.''; PubMed
  20. Wang W.; ''Emergence of a DNA-damage response network consisting of Fanconi anaemia and BRCA proteins.''; PubMed
  21. Marteijn JA, Lans H, Vermeulen W, Hoeijmakers JH.; ''Understanding nucleotide excision repair and its roles in cancer and ageing.''; PubMed
  22. Kim JM, Kee Y, Gurtan A, D'Andrea AD.; ''Cell cycle-dependent chromatin loading of the Fanconi anemia core complex by FANCM/FAAP24.''; PubMed
  23. Machida YJ, Machida Y, Chen Y, Gurtan AM, Kupfer GM, D'Andrea AD, Dutta A.; ''UBE2T is the E2 in the Fanconi anemia pathway and undergoes negative autoregulation.''; PubMed
  24. Yan Z, Delannoy M, Ling C, Daee D, Osman F, Muniandy PA, Shen X, Oostra AB, Du H, Steltenpool J, Lin T, Schuster B, Décaillet C, Stasiak A, Stasiak AZ, Stone S, Hoatlin ME, Schindler D, Woodcock CL, Joenje H, Sen R, de Winter JP, Li L, Seidman MM, Whitby MC, Myung K, Constantinou A, Wang W.; ''A histone-fold complex and FANCM form a conserved DNA-remodeling complex to maintain genome stability.''; PubMed
  25. Yamamoto KN, Kobayashi S, Tsuda M, Kurumizaka H, Takata M, Kono K, Jiricny J, Takeda S, Hirota K.; ''Involvement of SLX4 in interstrand cross-link repair is regulated by the Fanconi anemia pathway.''; PubMed
  26. Wang R, Persky NS, Yoo B, Ouerfelli O, Smogorzewska A, Elledge SJ, Pavletich NP.; ''DNA repair. Mechanism of DNA interstrand cross-link processing by repair nuclease FAN1.''; PubMed
  27. Alpi A, Langevin F, Mosedale G, Machida YJ, Dutta A, Patel KJ.; ''UBE2T, the Fanconi anemia core complex, and FANCD2 are recruited independently to chromatin: a basis for the regulation of FANCD2 monoubiquitination.''; PubMed
  28. Ishiai M, Kimura M, Namikoshi K, Yamazoe M, Yamamoto K, Arakawa H, Agematsu K, Matsushita N, Takeda S, Buerstedde JM, Takata M.; ''DNA cross-link repair protein SNM1A interacts with PIAS1 in nuclear focus formation.''; PubMed
  29. Hodson C, Purkiss A, Miles JA, Walden H.; ''Structure of the human FANCL RING-Ube2T complex reveals determinants of cognate E3-E2 selection.''; PubMed
  30. Garcia-Higuera I, Taniguchi T, Ganesan S, Meyn MS, Timmers C, Hejna J, Grompe M, D'Andrea AD.; ''Interaction of the Fanconi anemia proteins and BRCA1 in a common pathway.''; PubMed
  31. Tomida J, Itaya A, Shigechi T, Unno J, Uchida E, Ikura M, Masuda Y, Matsuda S, Adachi J, Kobayashi M, Meetei AR, Maehara Y, Yamamoto K, Kamiya K, Matsuura A, Matsuda T, Ikura T, Ishiai M, Takata M.; ''A novel interplay between the Fanconi anemia core complex and ATR-ATRIP kinase during DNA cross-link repair.''; PubMed
  32. Longerich S, San Filippo J, Liu D, Sung P.; ''FANCI binds branched DNA and is monoubiquitinated by UBE2T-FANCL.''; PubMed
  33. Fekairi S, Scaglione S, Chahwan C, Taylor ER, Tissier A, Coulon S, Dong MQ, Ruse C, Yates JR, Russell P, Fuchs RP, McGowan CH, Gaillard PH.; ''Human SLX4 is a Holliday junction resolvase subunit that binds multiple DNA repair/recombination endonucleases.''; PubMed
  34. Ho GP, Margossian S, Taniguchi T, D'Andrea AD.; ''Phosphorylation of FANCD2 on two novel sites is required for mitomycin C resistance.''; PubMed
  35. Rothkamm K, Krüger I, Thompson LH, Löbrich M.; ''Pathways of DNA double-strand break repair during the mammalian cell cycle.''; PubMed
  36. Singh TR, Saro D, Ali AM, Zheng XF, Du CH, Killen MW, Sachpatzidis A, Wahengbam K, Pierce AJ, Xiong Y, Sung P, Meetei AR.; ''MHF1-MHF2, a histone-fold-containing protein complex, participates in the Fanconi anemia pathway via FANCM.''; PubMed
  37. Ciccia A, Ling C, Coulthard R, Yan Z, Xue Y, Meetei AR, Laghmani el H, Joenje H, McDonald N, de Winter JP, Wang W, West SC.; ''Identification of FAAP24, a Fanconi anemia core complex protein that interacts with FANCM.''; PubMed
  38. Jiang Q, Greenberg RA.; ''Deciphering the BRCA1 Tumor Suppressor Network.''; PubMed
  39. Cohn MA, Kowal P, Yang K, Haas W, Huang TT, Gygi SP, D'Andrea AD.; ''A UAF1-containing multisubunit protein complex regulates the Fanconi anemia pathway.''; PubMed
  40. Unsal-Kaçmaz K, Sancar A.; ''Quaternary structure of ATR and effects of ATRIP and replication protein A on its DNA binding and kinase activities.''; PubMed
  41. Sato K, Toda K, Ishiai M, Takata M, Kurumizaka H.; ''DNA robustly stimulates FANCD2 monoubiquitylation in the complex with FANCI.''; PubMed
  42. Huang M, Kim JM, Shiotani B, Yang K, Zou L, D'Andrea AD.; ''The FANCM/FAAP24 complex is required for the DNA interstrand crosslink-induced checkpoint response.''; PubMed
  43. MacKay C, Déclais AC, Lundin C, Agostinho A, Deans AJ, MacArtney TJ, Hofmann K, Gartner A, West SC, Helleday T, Lilley DM, Rouse J.; ''Identification of KIAA1018/FAN1, a DNA repair nuclease recruited to DNA damage by monoubiquitinated FANCD2.''; PubMed
  44. Sengerová B, Allerston CK, Abu M, Lee SY, Hartley J, Kiakos K, Schofield CJ, Hartley JA, Gileadi O, McHugh PJ.; ''Characterization of the human SNM1A and SNM1B/Apollo DNA repair exonucleases.''; PubMed
  45. Ciccia A, Elledge SJ.; ''The DNA damage response: making it safe to play with knives.''; PubMed
  46. Yuan F, El Hokayem J, Zhou W, Zhang Y.; ''FANCI protein binds to DNA and interacts with FANCD2 to recognize branched structures.''; PubMed
  47. Tao Y, Jin C, Li X, Qi S, Chu L, Niu L, Yao X, Teng M.; ''The structure of the FANCM-MHF complex reveals physical features for functional assembly.''; PubMed
  48. Ishiai M, Kitao H, Smogorzewska A, Tomida J, Kinomura A, Uchida E, Saberi A, Kinoshita E, Kinoshita-Kikuta E, Koike T, Tashiro S, Elledge SJ, Takata M.; ''FANCI phosphorylation functions as a molecular switch to turn on the Fanconi anemia pathway.''; PubMed
  49. Liu T, Ghosal G, Yuan J, Chen J, Huang J.; ''FAN1 acts with FANCI-FANCD2 to promote DNA interstrand cross-link repair.''; PubMed
  50. Vermeulen W, Fousteri M.; ''Mammalian transcription-coupled excision repair.''; PubMed
  51. Klein Douwel D, Boonen RA, Long DT, Szypowska AA, Räschle M, Walter JC, Knipscheer P.; ''XPF-ERCC1 acts in Unhooking DNA interstrand crosslinks in cooperation with FANCD2 and FANCP/SLX4.''; PubMed
  52. Wyatt HD, Sarbajna S, Matos J, West SC.; ''Coordinated actions of SLX1-SLX4 and MUS81-EME1 for Holliday junction resolution in human cells.''; PubMed
  53. Kottemann MC, Smogorzewska A.; ''Fanconi anaemia and the repair of Watson and Crick DNA crosslinks.''; PubMed
  54. Moldovan GL, Madhavan MV, Mirchandani KD, McCaffrey RM, Vinciguerra P, D'Andrea AD.; ''DNA polymerase POLN participates in cross-link repair and homologous recombination.''; PubMed
  55. Zhao Q, Xue X, Longerich S, Sung P, Xiong Y.; ''Structural insights into 5' flap DNA unwinding and incision by the human FAN1 dimer.''; PubMed
  56. Yang K, Moldovan GL, D'Andrea AD.; ''RAD18-dependent recruitment of SNM1A to DNA repair complexes by a ubiquitin-binding zinc finger.''; PubMed
  57. Friedberg EC.; ''How nucleotide excision repair protects against cancer.''; PubMed
  58. Smogorzewska A, Desetty R, Saito TT, Schlabach M, Lach FP, Sowa ME, Clark AB, Kunkel TA, Harper JW, Colaiácovo MP, Elledge SJ.; ''A genetic screen identifies FAN1, a Fanconi anemia-associated nuclease necessary for DNA interstrand crosslink repair.''; PubMed


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101549view11:41, 1 November 2018ReactomeTeamreactome version 66
101084view21:24, 31 October 2018ReactomeTeamreactome version 65
100613view19:58, 31 October 2018ReactomeTeamreactome version 64
100164view16:43, 31 October 2018ReactomeTeamreactome version 63
99714view15:11, 31 October 2018ReactomeTeamreactome version 62 (2nd attempt)
96986view06:49, 25 April 2018Fehrhartfixed a weird connection
93977view13:49, 16 August 2017ReactomeTeamreactome version 61
93579view11:27, 9 August 2017ReactomeTeamreactome version 61
87446view13:44, 22 July 2016MkutmonOntology Term : 'disease pathway' added !
87445view13:43, 22 July 2016MkutmonOntology Term : 'Fanconi's anemia' added !
87444view13:43, 22 July 2016MkutmonOntology Term : 'DNA repair pathway' added !
86685view09:24, 11 July 2016ReactomeTeamreactome version 56
83459view12:28, 18 November 2015ReactomeTeamNew pathway

External references


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NameTypeDatabase referenceComment
ADPMetaboliteCHEBI:16761 (ChEBI)
APITD1 ProteinQ8N2Z9 (Uniprot-TrEMBL)
APITD1:STRA13 octamerComplexR-HSA-6785093 (Reactome)
ATPMetaboliteCHEBI:15422 (ChEBI)
ATR ProteinQ13535 (Uniprot-TrEMBL)
ATR:ATRIPComplexR-HSA-176269 (Reactome) The ATR (ATM- and rad3-related) kinase is an essential checkpoint factor in human cells. In response to replication stress (i.e., stresses that cause replication fork stalling) or ultraviolet radiation, ATR becomes active and phosphorylates numerous factors involved in the checkpoint response including the checkpoint kinase Chk1. ATR is invariably associated with ATRIP (ATR-interacting protein) in human cells. Depletion of ATRIP by siRNA causes a loss of ATR without affecting ATR mRNA levels indicating that complex formation stabilizes ATR. ATRIP is also a substrate for the ATR kinase, but this modification does not play a significant role in the recruitment of ATR-ATRIP to sites of damage, the activation of Chk1, or the modification of p53.
ATRIP ProteinQ8WXE1 (Uniprot-TrEMBL)
DCLRE1A ProteinQ6PJP8 (Uniprot-TrEMBL)
DCLRE1A,DCLRE1BComplexR-HSA-6785737 (Reactome)
DCLRE1B ProteinQ9H816 (Uniprot-TrEMBL)
DNA Double-Strand Break RepairPathwayR-HSA-5693532 (Reactome) Double-strand breaks (DSBs), one of the most deleterious types of DNA damage along with interstrand crosslinks, are caused by ionizing radiation or certain chemicals such as bleomycin. DSBs also occur physiologically, during the processes of DNA replication, meiotic exchange, and V(D)J recombination.

DSBs are sensed (detected) by the MRN complex. Binding of the MRN complex to the DSBs usually triggers ATM kinase activation, thus initiating the DNA double strand break response. ATM phosphorylates a number of proteins involved in DNA damage checkpoint signaling, as well as proteins directly involved in the repair of DNA DSBs. DSBs are repaired via homology directed repair (HDR) or via nonhomologous end-joining (NHEJ).

HDR requires resection of DNA DSB ends. Resection creates 3'-ssDNA overhangs which then anneal with a homologous DNA sequence. This homologous sequence can then be used as a template for DNA repair synthesis that bridges the DSB. HDR preferably occurs through the error-free homologous recombination repair (HRR), but can also occur through the error-prone single strand annealing (SSA), or the least accurate microhomology-mediated end joining (MMEJ). MMEJ takes place when DSB response cannot be initiated.

While HRR is limited to actively dividing cells with replicated DNA, error-prone NHEJ pathway functions at all stages of the cell cycle, playing the predominant role in both the G1 phase and in S-phase regions of DNA that have not yet replicated. During NHEJ, the Ku70:Ku80 heterodimer (also known as the Ku complex or XRCC5:XRCC6) binds DNA DSB ends, competing away the MRN complex and preventing MRN-mediated resection of DNA DSB ends. The catalytic subunit of the DNA-dependent protein kinase (DNA-PKcs, PRKDC) is then recruited to DNA-bound Ku to form the DNA-PK holoenzyme. Two DNA-PK complexes, one at each side of the break, bring DNA DSB ends together, joining them in a synaptic complex. DNA-PK complex recruits DCLRE1C (ARTEMIS) to DNA DSB ends, leading to trimming of 3'- and 5'-overhangs at the break site, followed by ligation.

For review of this topic, please refer to Ciccia and Elledge 2010.

DNA double-strand break endsR-ALL-75165 (Reactome)
Distorted dsDNAR-ALL-5688114 (Reactome)
EME1 ProteinQ96AY2 (Uniprot-TrEMBL)
EME2 ProteinA4GXA9 (Uniprot-TrEMBL)
ERCC1 ProteinP07992 (Uniprot-TrEMBL)
ERCC1:ERCC4ComplexR-HSA-109943 (Reactome)
ERCC4 ProteinQ92889 (Uniprot-TrEMBL)
FA Core Complex:ICL-DNAComplexR-HSA-6785124 (Reactome)
FAAP100 ProteinQ0VG06 (Uniprot-TrEMBL)
FAAP100ProteinQ0VG06 (Uniprot-TrEMBL)
FAAP20 ProteinQ6NZ36 (Uniprot-TrEMBL)
FAAP20ProteinQ6NZ36 (Uniprot-TrEMBL)
FAAP24 ProteinQ9BTP7 (Uniprot-TrEMBL)
FAAP24ProteinQ9BTP7 (Uniprot-TrEMBL)
FAN1 ProteinQ9Y2M0 (Uniprot-TrEMBL)
FAN1ProteinQ9Y2M0 (Uniprot-TrEMBL)
FANCA ProteinO15360 (Uniprot-TrEMBL)
FANCAProteinO15360 (Uniprot-TrEMBL)
FANCB ProteinQ8NB91 (Uniprot-TrEMBL)
FANCBProteinQ8NB91 (Uniprot-TrEMBL)
FANCC ProteinQ00597 (Uniprot-TrEMBL)
FANCCProteinQ00597 (Uniprot-TrEMBL)
FANCD2 ProteinQ9BXW9 (Uniprot-TrEMBL)
FANCD2:FANCI:UBE2T:FA Core Complex:ICL-DNA:RPA:ATR:ATRIPComplexR-HSA-6788386 (Reactome)
FANCD2:FANCI:UBE2T:FA Core Complex:ICL-DNAComplexR-HSA-6785340 (Reactome)
FANCD2:FANCIComplexR-HSA-420764 (Reactome)
FANCD2ProteinQ9BXW9 (Uniprot-TrEMBL)
FANCE ProteinQ9HB96 (Uniprot-TrEMBL)
FANCEProteinQ9HB96 (Uniprot-TrEMBL)
FANCF ProteinQ9NPI8 (Uniprot-TrEMBL)
FANCFProteinQ9NPI8 (Uniprot-TrEMBL)
FANCG ProteinO15287 (Uniprot-TrEMBL)
FANCGProteinO15287 (Uniprot-TrEMBL)
FANCI ProteinQ9NVI1 (Uniprot-TrEMBL)
FANCIProteinQ9NVI1 (Uniprot-TrEMBL)
FANCL ProteinQ9NW38 (Uniprot-TrEMBL)
FANCLProteinQ9NW38 (Uniprot-TrEMBL)
FANCM ProteinQ8IYD8 (Uniprot-TrEMBL)
FANCM:FAAP24:APITD1:STRA13:ICL-DNAComplexR-HSA-6785090 (Reactome)
FANCM:FAAP24ComplexR-HSA-6785088 (Reactome)
FANCMProteinQ8IYD8 (Uniprot-TrEMBL)
ICL-DNA R-HSA-6785117 (Reactome)
ICL-DNAR-HSA-6785117 (Reactome)
MUS81 ProteinQ96NY9 (Uniprot-TrEMBL)
MonoUb-K523,p-4S-FANCI ProteinQ9NVI1 (Uniprot-TrEMBL)
MonoUb-K561,p-T691,S717-FANCD2 ProteinQ9BXW9 (Uniprot-TrEMBL)
MonoUb-K91,K182-UBE2T ProteinQ9NPD8 (Uniprot-TrEMBL)
MonoUb:K561,p-T691,S717-FANCD2:MonoUb:K523,p-4S-FANCI:FA Core Complex:ICL-DNA:Unhooking nucleasesComplexR-HSA-6785734 (Reactome)
MonoUb:K561,p-T691,S717-FANCD2:MonoUb:K523,p-4S-FANCI:FA Core Complex:ICL-DNAComplexR-HSA-6785367 (Reactome)
MonoUb:K561,p-T691,S717-FANCD2:MonoUb:K523,p-4S-FANCI:FA Core Complex:Unhooked ICL-DNA:POLNComplexR-HSA-6786156 (Reactome)
MonoUb:K561,p-T691,S717-FANCD2:MonoUb:K523,p-4S-FANCI:FA Core Complex:Unhooked ICL-DNAComplexR-HSA-6786151 (Reactome)
MonoUb:K561,p-T691,S717-FANCD2:MonoUb:K523,p-4S-FANCIComplexR-HSA-420757 (Reactome)
MonoUb:K91,K182-UBE2TComplexR-HSA-6785366 (Reactome)
Nucleotide Excision RepairPathwayR-HSA-5696398 (Reactome) Nucleotide excision repair (NER) was first described in the model organism E. coli in the early 1960s as a process whereby bulky base damage is enzymatically removed from DNA, facilitating the recovery of DNA synthesis and cell survival. Deficient NER processes have been identified from the cells of cancer-prone patients with different variants of xeroderma pigmentosum (XP), trichothiodystrophy (TTD), and Cockayne's syndrome. The XP cells exhibit an ultraviolet radiation hypersensitivity that leads to a hypermutability response to UV, offering a direct connection between deficient NER, increased mutation rate, and cancer. While the NER pathway in prokaryotes is unique, the pathway utilized in yeast and higher eukaryotes is highly conserved.
NER is involved in the repair of bulky adducts in DNA, such as UV-induced photo lesions (both 6-4 photoproducts (6-4 PPDs) and cyclobutane pyrimidine dimers (CPDs)), as well as chemical adducts formed from exposure to aflatoxin, benzopyrene and other genotoxic agents. Specific proteins have been identified that participate in base damage recognition, cleavage of the damaged strand on both sides of the lesion, and excision of the oligonucleotide bearing the lesion. Reparative DNA synthesis and ligation restore the strand to its original state.
NER consists of two related pathways called global genome nucleotide excision repair (GG-NER) and transcription-coupled nucleotide excision repair (TC-NER). The pathways differ in the way in which DNA damage is initially recognized, but the majority of the participating molecules are shared between these two branches of NER. GG-NER is transcription-independent, removing lesions from non-coding DNA strands, as well as coding DNA strands that are not being actively transcribed. TC-NER repairs damage in transcribed strands of active genes.
Several of the proteins involved in NER are key components of the basal transcription complex TFIIH. An ubiquitin ligase complex composed of DDB1, CUL4A or CUL4B and RBX1 participates in both GG-NER and TC-NER, implying an important role of ubiquitination in NER regulation. The establishment of mutant mouse models for NER genes and other DNA repair-related genes has been useful in demonstrating the associations between NER defects and cancer.
For past and recent reviews of nucleotide excision repair, please refer to Lindahl and Wood 1998, Friedberg et al. 2002, Christmann et al. 2003, Hanawalt and Spivak 2008, Marteijn et al. 2014).
POLN ProteinQ7Z5Q5 (Uniprot-TrEMBL)
POLNProteinQ7Z5Q5 (Uniprot-TrEMBL)
PPiMetaboliteCHEBI:29888 (ChEBI)
RPA heterotrimerComplexR-HSA-68462 (Reactome)
RPA1 ProteinP27694 (Uniprot-TrEMBL)
RPA2 ProteinP15927 (Uniprot-TrEMBL)
RPA3 ProteinP35244 (Uniprot-TrEMBL)
RPS27A(1-76) ProteinP62979 (Uniprot-TrEMBL)
SLX1A ProteinQ9BQ83 (Uniprot-TrEMBL)
SLX1A:SLX4:MUS81:EME1,(MUS81:EME2)ComplexR-HSA-5686474 (Reactome)
SLX4 ProteinQ8IY92 (Uniprot-TrEMBL)
STRA13 ProteinA8MT69 (Uniprot-TrEMBL)
UBA52(1-76) ProteinP62987 (Uniprot-TrEMBL)
UBB(1-76) ProteinP0CG47 (Uniprot-TrEMBL)
UBB(153-228) ProteinP0CG47 (Uniprot-TrEMBL)
UBB(77-152) ProteinP0CG47 (Uniprot-TrEMBL)
UBC(1-76) ProteinP0CG48 (Uniprot-TrEMBL)
UBC(153-228) ProteinP0CG48 (Uniprot-TrEMBL)
UBC(229-304) ProteinP0CG48 (Uniprot-TrEMBL)
UBC(305-380) ProteinP0CG48 (Uniprot-TrEMBL)
UBC(381-456) ProteinP0CG48 (Uniprot-TrEMBL)
UBC(457-532) ProteinP0CG48 (Uniprot-TrEMBL)
UBC(533-608) ProteinP0CG48 (Uniprot-TrEMBL)
UBC(609-684) ProteinP0CG48 (Uniprot-TrEMBL)
UBC(77-152) ProteinP0CG48 (Uniprot-TrEMBL)
UBE2T ProteinQ9NPD8 (Uniprot-TrEMBL)
UBE2TProteinQ9NPD8 (Uniprot-TrEMBL)
USP1 ProteinO94782 (Uniprot-TrEMBL)
USP1:WDR48ComplexR-HSA-419551 (Reactome)
UbComplexR-HSA-68524 (Reactome)
Unhooked ICL-DNA R-HSA-6786149 (Reactome)
WDR48 ProteinQ8TAF3 (Uniprot-TrEMBL)
dNTPMetaboliteCHEBI:16516 (ChEBI)
p-4S-FANCI ProteinQ9NVI1 (Uniprot-TrEMBL)
p-FA Core Complex:ICL-DNAComplexR-HSA-6788397 (Reactome)
p-FA Core ComplexComplexR-HSA-6788399 (Reactome)
p-FANCD2:p-FANCI:UBE2T:p-FA Core Complex:ICL-DNAComplexR-HSA-6788398 (Reactome)
p-FANCD2:p-FANCIComplexR-HSA-6788402 (Reactome)
p-RPA heterotrimerComplexR-HSA-5685169 (Reactome)
p-S1045-FANCM ProteinQ8IYD8 (Uniprot-TrEMBL)
p-S33-RPA2 ProteinP15927 (Uniprot-TrEMBL)
p-T691,S717-FANCD2 ProteinQ9BXW9 (Uniprot-TrEMBL)

Annotated Interactions

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SourceTargetTypeDatabase referenceComment
ADPArrowR-HSA-6788392 (Reactome)
APITD1:STRA13 octamerR-HSA-6785087 (Reactome)
ATPR-HSA-6788392 (Reactome)
ATR:ATRIPArrowR-HSA-6788392 (Reactome)
ATR:ATRIPR-HSA-6788385 (Reactome)
DCLRE1A,DCLRE1BArrowR-HSA-6785986 (Reactome)
DCLRE1A,DCLRE1BR-HSA-6785732 (Reactome)
DNA double-strand break endsArrowR-HSA-6786166 (Reactome)
Distorted dsDNAArrowR-HSA-6786166 (Reactome)
ERCC1:ERCC4ArrowR-HSA-6785986 (Reactome)
ERCC1:ERCC4R-HSA-6785732 (Reactome)
FA Core Complex:ICL-DNAArrowR-HSA-6785126 (Reactome)
FA Core Complex:ICL-DNAR-HSA-6785342 (Reactome)
FAAP100R-HSA-6785126 (Reactome)
FAAP20R-HSA-6785126 (Reactome)
FAAP24R-HSA-6785607 (Reactome)
FAN1ArrowR-HSA-6785986 (Reactome)
FAN1R-HSA-6785732 (Reactome)
FANCAR-HSA-6785126 (Reactome)
FANCBR-HSA-6785126 (Reactome)
FANCCR-HSA-6785126 (Reactome)
FANCD2:FANCI:UBE2T:FA Core Complex:ICL-DNA:RPA:ATR:ATRIPArrowR-HSA-6788385 (Reactome)
FANCD2:FANCI:UBE2T:FA Core Complex:ICL-DNA:RPA:ATR:ATRIPR-HSA-6788392 (Reactome)
FANCD2:FANCI:UBE2T:FA Core Complex:ICL-DNA:RPA:ATR:ATRIPmim-catalysisR-HSA-6788392 (Reactome)
FANCD2:FANCI:UBE2T:FA Core Complex:ICL-DNAArrowR-HSA-6785342 (Reactome)
FANCD2:FANCI:UBE2T:FA Core Complex:ICL-DNAR-HSA-6788385 (Reactome)
FANCD2:FANCIArrowR-HSA-6785594 (Reactome)
FANCD2:FANCIR-HSA-6785342 (Reactome)
FANCD2R-HSA-6785594 (Reactome)
FANCER-HSA-6785126 (Reactome)
FANCFR-HSA-6785126 (Reactome)
FANCGR-HSA-6785126 (Reactome)
FANCIR-HSA-6785594 (Reactome)
FANCLR-HSA-6785126 (Reactome)
FANCM:FAAP24:APITD1:STRA13:ICL-DNAArrowR-HSA-6785087 (Reactome)
FANCM:FAAP24:APITD1:STRA13:ICL-DNAR-HSA-6785126 (Reactome)
FANCM:FAAP24ArrowR-HSA-6785607 (Reactome)
FANCM:FAAP24R-HSA-6785087 (Reactome)
FANCMR-HSA-6785607 (Reactome)
ICL-DNAR-HSA-6785087 (Reactome)
MonoUb:K561,p-T691,S717-FANCD2:MonoUb:K523,p-4S-FANCI:FA Core Complex:ICL-DNA:Unhooking nucleasesArrowR-HSA-6785732 (Reactome)
MonoUb:K561,p-T691,S717-FANCD2:MonoUb:K523,p-4S-FANCI:FA Core Complex:ICL-DNA:Unhooking nucleasesR-HSA-6785986 (Reactome)
MonoUb:K561,p-T691,S717-FANCD2:MonoUb:K523,p-4S-FANCI:FA Core Complex:ICL-DNA:Unhooking nucleasesmim-catalysisR-HSA-6785986 (Reactome)
MonoUb:K561,p-T691,S717-FANCD2:MonoUb:K523,p-4S-FANCI:FA Core Complex:ICL-DNAArrowR-HSA-6785361 (Reactome)
MonoUb:K561,p-T691,S717-FANCD2:MonoUb:K523,p-4S-FANCI:FA Core Complex:ICL-DNAR-HSA-6785732 (Reactome)
MonoUb:K561,p-T691,S717-FANCD2:MonoUb:K523,p-4S-FANCI:FA Core Complex:ICL-DNAR-HSA-6786171 (Reactome)
MonoUb:K561,p-T691,S717-FANCD2:MonoUb:K523,p-4S-FANCI:FA Core Complex:Unhooked ICL-DNA:POLNArrowR-HSA-6786155 (Reactome)
MonoUb:K561,p-T691,S717-FANCD2:MonoUb:K523,p-4S-FANCI:FA Core Complex:Unhooked ICL-DNA:POLNR-HSA-6786166 (Reactome)
MonoUb:K561,p-T691,S717-FANCD2:MonoUb:K523,p-4S-FANCI:FA Core Complex:Unhooked ICL-DNA:POLNmim-catalysisR-HSA-6786166 (Reactome)
MonoUb:K561,p-T691,S717-FANCD2:MonoUb:K523,p-4S-FANCI:FA Core Complex:Unhooked ICL-DNAArrowR-HSA-6785986 (Reactome)
MonoUb:K561,p-T691,S717-FANCD2:MonoUb:K523,p-4S-FANCI:FA Core Complex:Unhooked ICL-DNAR-HSA-6786155 (Reactome)
MonoUb:K561,p-T691,S717-FANCD2:MonoUb:K523,p-4S-FANCIArrowR-HSA-6786166 (Reactome)
MonoUb:K91,K182-UBE2TArrowR-HSA-6785361 (Reactome)
POLNArrowR-HSA-6786166 (Reactome)
POLNR-HSA-6786155 (Reactome)
PPiArrowR-HSA-6786166 (Reactome)
R-HSA-6785087 (Reactome) A complex composed of FANCM and FAAP24 is constitutively associated with chromatin (Ciccia et al. 2007, Kim et al. 2008). Chromatin localization of the FANCM:FAAP24 complex is facilitated by the octameric MHF complex (Tao et al. 2012) composed of four dimers of two histone-like proteins: APITD1 (MHF1, FAAP16) and STRA13 (MHF2, FAAP10) (Singh et al. 2010). The complex of FANCM, FAAP24, APITD1 and STRA13 may constitute a molecular machine that preferentially binds to replication forks stalled at DNA interstrand crosslinks (ICL-DNA), with FANCM preferentially binding to the branch point, FAAP24 to the single strand DNA (ssDNA) and the MHF complex to the double strand DNA (Yan et al. 2010).
R-HSA-6785126 (Reactome) In addition to FANCM, FAAP24, APITD1 (MHF1) and STRA13 (MHF2), the FA core complex also includes FANCA, FANCB, FANCC, FANCE, FANCF, FANCG, FANCL, FAAP20 and FAAP100 (Singh et al. 2010, Yan et al. 2010, Leung et al. 2012). While FANCA, FANCB, FANCC, FANCE, FANCF, FANCG and FANCL, and probably FAAP20 and FAAP100, can assemble a complex in the nucleoplasm, they are unable to load onto DNA in the absence of FANCM and FAAP24 (Kim et al. 2008, Yan et al. 2010, Leung et al. 2012).
R-HSA-6785342 (Reactome) The ID2 complex, composed of FANCD2 and FANCI, binds to branched DNA structures, such as stalled replication forks at DNA interstrand crosslinks (ICL-DNA) (Yuan et al. 2009, Longerich et al. 2009, Joo et al. 2011). The ID2 complex also interacts with the FA core complex component FANCL, activating the E3 ubiquitin ligase activity of FANCL (Rajendra et al. 2014, Longerich et al. 2014). Up to fifty FANCD2 molecules (ID2 complexes) may be recruited per one ICL, probably spreading to surrounding DNA (Douwel et al. 2014). The E2 ubiquitin ligase UBE2T is recruited to ICL-DNA by binding to the FANCL subunit of the FA core complex independently of the ID2 complex (Machida et al. 2006, Alpi et al. 2007, Hodson et al. 2014).
R-HSA-6785361 (Reactome) FANCD2 and FANCI, the components of the ID2 complex, are monoubiquitinated at DNA interstrand crosslinks (ICL-DNA) by the coordinated action of the E2 ubiquitin ligase UBE2T and the E3 ubiquitin ligase FANCL (Machida et al. 2006, Alpi et al. 2007, Sims et al. 2007, Smogorzewska et al. 2007, Longerich et al. 2009, Sato et al. 2012, Hodson et al. 2014). FANCL achieves the maximal catalytic activity as part of the ICL-DNA-bound FA core complex, and requires the presence of at least FANCB and FAAP100 subunits of the FA core complex to monoubiquitinate the ID2 complex (Rajendra et al. 2014, Longerich et al. 2014). FANCD2 is monoubiquitinated on lysine residue K561, while FANCI is monoubiquitinated on lysine residue K523 (Alpi et al. 2008, Longerich et al. 2014). In the absence of FANCD2, a DNA-bound FANCI can be monoubiquitinated in a FANCL-independent manner (Longerich et al. 2014).

UBE2T is also monoubiqutinated by FANCL on lysine residues K91 and K182 during the process of ID2 monoubiquitination. Monoubiquitination of UBE2T may serve as a self-inactivating mechanism that negatively regulates the Fanconi anemia pathway (Machida et al. 2006).

FANCD2 monoubiquitination promotes stability of the ID2 complex and its retention at ICL-DNA, and enables recruitment of additional proteins that participate in the repair of ICL-DNA (Garcia-Higuera et al. 2001, Smogorzewska et al. 2007, Alpi et al. 2008, Joo et al. 2011).

R-HSA-6785594 (Reactome) FANCD2 binds FANCI, forming the ID2 complex (Yuan et al. 2009, Joo et al. 2011). The ID2 complex plays an important role in the repair of DNA interstrand crosslinks (the Fanconi anemia pathway).
R-HSA-6785607 (Reactome) FANCM binds FAAP24, forming a complex that recognizes DNA interstrand crosslinks, thus triggering the Fanconi anemia repair pathway (Ciccia et al. 2007, Kim et al. 2008).
R-HSA-6785732 (Reactome) Several DNA nucleases bind to interstrand crosslinks (ICL-DNA) and participate in ICL "unhooking". The ubiquitin-binding zinc finger (UBZ) domain of the DNA nuclease FAN1 binds to monoubiquitinated FANCD2, enabling the recruitment of FAN1 to the ICL-DNA repair site (Liu et al. 2010, MacKay et al. 2010, Smogorzewska et al. 2010, Kratz et al. 2010). Once recruited to ICL-DNA, FAN1 forms head-to-tail homodimers. Homodimerization is important for the endonucleolytic activity of FAN1 (Zhao et al. 2014). SLX4 (FANCP) serves as a docking platform for recruitment of SLX1A, MUS81 and EME1 or EME2, resulting in formation of the SLX1A:SLX4:MUS81:EME1 (or SLX1A:SLX4:MUS81:EME2) endonucleolytic complex (Fekairi et al. 2009, Wyatt et al. 2013). SLX4 can also bind the endonucleolytic complex composed of ERCC1 and ERCC4 (XPF) (Fekairi et al. 2009). SLX4 is recruited to ICL-DNA through interaction of the UBZ domain of SLX4 with monoubiquitinated FANCD2 (Yamamoto et al. 2011). Targeted deletion of the UBZ domain of SLX4 confers sensitivity to ICL-inducing agents, but the UBZ domain seems to be dispensable for the role of SLX4 in homologous recombination repair (Yamamoto et al. 2011).

DNA exonucleases DCLRE1A (SNM1A) and DCLRE1B (SNM1B) likely function redundantly in ICL repair. Similar to FAN1, they are able to digest the DNA past the ICL, thereby unhooking one of the DNA strands (Wang et al. 2011, Sengerova et al. 2012). Monoubiquitination of the PCNA subunit of the stalled replicative polymerase complex by RAD18 may provide the docking site for DCLRE1A (or DCLRE1B) (Yang et al. 2010). In addition, PIAS1 may facilitate loading of DCLRE1A (or DCLRE1B) to ICL sites (Ishiai et al. 2004).

R-HSA-6785986 (Reactome) Unhooking of interstrand crosslinks (ICLs) from damaged DNA (ICL-DNA) involves coordinated action of several DNA nucleases: FAN1, DCLRE1A or DCLRE1B, the complex of ERCC1 and ERCC4 (XPF), and the complex of SLX4 (FANCP), SLX1A, MUS81 and EME1 or EME2. These DNA nucleases incise ICL-DNA at both sides of the ICL, thus removing the covalent bond between the two DNA strands. The exact sequence of incision steps has not been determined and it is possible that some of the implicated nucleases act in a redundant manner.

FAN1 exhibits 5'->3' endonuclease activity, as well as 5'->3' exonuclease activity, with a preference for 5' flaps and branched DNA structures (Smogorzewska et al. 2010, Kratz et al. 2010, MacKay et al. 2010, Liu et al. 2010). The FAN1 head-to-tail homodimer recognizes the lesion, orients and unwinds the 5' flap (Zhao et al. 2014). FAN1 requires a 5' terminal phosphate anchor and successively cleaves the DNA at every third nucleotide (Wang et al. 2014). This suggests that an incision 5' to the ICL precedes the action of FAN1.

ERCC4 (XPF) in complex with ERCC1 may perform the first endonucleolytic incision 5' to the ICL (Wang et al. 2011), while MUS81 in complex with EME1 or EME2 may act as a backup endonuclease. DCLRE1A (SNM1A) exhibits a 5'->3' exonuclease activity and can digest past the ICL, thereby unhooking it from one DNA strand after the ERCC1:ERCC4 complex does the initial incision 5' to the ICL (Wang et al. 2011). DCLRE1A functions redundantly with DCLRE1B (SNM1B) in ICL repair (Ishiai et al. 2004, Sangerova et al. 2012).

R-HSA-6786155 (Reactome) An error-prone DNA polymerase nu (POLN) is recruited to the interstrand crosslink (ICL) repair site through interaction with monoubiquitinated FANCD2 and probably the PCNA subunit of the stalled replication complex (Moldovan et al. 2010).
R-HSA-6786166 (Reactome) The error-prone DNA polymerase nu (POLN) performs translesion DNA synthesis using the DNA strand with unhooked interstrand crosslink (ICL) as a template, thereby bypassing the unhooked ICL (Moldovan et al. 2010, Yamanaka et al. 2010). The DNA strand with unhooked ICL is subsequently repaired via nucleotide excision repair (NER), while the double strand break (DSB) generated by incision of the stalled replication fork during the unhooking step is repaired via homologous recombination repair (HRR) (reviewed by Kottemann and Smogorzewska 2013, Deans and West 2011).
R-HSA-6786171 (Reactome) The FA pathway is negatively regulated through the USP1:WDR48-mediated deubiquitination of FANCD2 (Nijman et al. 2005). WDR48 (UAF1) forms a complex with and activates USP1 (Cohn et al. 2007).
R-HSA-6788385 (Reactome) The complex of ATR and ATRIP (ATR:ATRIP) is recruited to replication forks blocked by DNA interstrand crosslinks (ICL-DNA) through interaction with the RPA complex and the Fanconi anemia (FA) core complex. The RPA heterotrimer associates both with single strand DNA (ssDNA) that is produced by DNA resection at ICL-DNA-stalled replication forks and with the FANCM and FAAP24 components of the FA core complex (Huang et al. 2010). ATRIP directly interacts with the FANCL component of the FA core complex (Tomida et al. 2013). The presence of RAD17 and TOPB1, which is required for ATR activation at DNA double strand breaks (DSBs), is not needed for ATR activation at ICL-DNA (Tomida et al. 2013).
R-HSA-6788392 (Reactome) ATR phosphorylates several proteins at DNA insterstrand crosslinks (ICL-DNA), with ATR activity at ICL-DNA being independent of the presence of RAD17 and TOPBP1 (Shigechi et al. 2012, Tomida et al. 2013). Besides phosphorylating the RPA2 subunit of the RPA heterotrimeric complex (Huang et al. 2010), activated ATR also phosphorylates the Fanconi anemia core complex component FANCM on serine residue S1045 (Singh et al. 2013). ATR-mediated phosphorylation of FANCM is thought to be important for the progression of ICL repair, although the mechanism is not known. The critical ATR substrate at ICL-DNA is considered to be FANCI component of the ID2 complex. ATR-mediated phosphorylation of FANCI, at least on serine residues S556, S559, S565 and S617, is a prerequisite for FANCD2 monoubiquitination (Ishiai et al. 2008, Shigechi et al. 2012). FANDC2 itself is also phosphorylated by ATR on threonine residue T691 and serine residue S717, which promotes FANCD2 monoubiquitination and enhances cellular resistance to DNA crosslinking agents (Ho et al. 2006).
RPA heterotrimerR-HSA-6788385 (Reactome)
SLX1A:SLX4:MUS81:EME1,(MUS81:EME2)ArrowR-HSA-6785986 (Reactome)
SLX1A:SLX4:MUS81:EME1,(MUS81:EME2)R-HSA-6785732 (Reactome)
UBE2TR-HSA-6785342 (Reactome)
USP1:WDR48TBarR-HSA-6785732 (Reactome)
USP1:WDR48mim-catalysisR-HSA-6786171 (Reactome)
UbArrowR-HSA-6786171 (Reactome)
UbR-HSA-6785361 (Reactome)
dNTPR-HSA-6786166 (Reactome)
p-FA Core Complex:ICL-DNAArrowR-HSA-6786171 (Reactome)
p-FA Core ComplexArrowR-HSA-6786166 (Reactome)
p-FANCD2:p-FANCI:UBE2T:p-FA Core Complex:ICL-DNAArrowR-HSA-6788392 (Reactome)
p-FANCD2:p-FANCI:UBE2T:p-FA Core Complex:ICL-DNAR-HSA-6785361 (Reactome)
p-FANCD2:p-FANCI:UBE2T:p-FA Core Complex:ICL-DNAmim-catalysisR-HSA-6785361 (Reactome)
p-FANCD2:p-FANCIArrowR-HSA-6786171 (Reactome)
p-RPA heterotrimerArrowR-HSA-6788392 (Reactome)

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