Fanconi Anemia Pathway (Homo sapiens)

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Description

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 ZBTB32 (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>

Comments

Reactome-Converter 
Pathway is converted from Reactome ID: 6783310
Reactome-version 
Reactome version: 61
Reactome Author 
Reactome Author: Matthews, Lisa

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Bibliography

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  42. Jiang Q, Greenberg RA.; ''Deciphering the BRCA1 Tumor Suppressor Network.''; PubMed
  43. 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
  44. 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
  45. 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
  46. 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
  47. 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
  48. 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
  49. 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
  50. Marteijn JA, Lans H, Vermeulen W, Hoeijmakers JH.; ''Understanding nucleotide excision repair and its roles in cancer and ageing.''; PubMed
  51. 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
  52. Christmann M, Tomicic MT, Roos WP, Kaina B.; ''Mechanisms of human DNA repair: an update.''; PubMed
  53. 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
  54. Yang K, Moldovan GL, D'Andrea AD.; ''RAD18-dependent recruitment of SNM1A to DNA repair complexes by a ubiquitin-binding zinc finger.''; PubMed
  55. Evans MK, Longo DL.; ''PALB2 mutations and breast-cancer risk.''; PubMed
  56. Sato K, Toda K, Ishiai M, Takata M, Kurumizaka H.; ''DNA robustly stimulates FANCD2 monoubiquitylation in the complex with FANCI.''; PubMed
  57. Wyatt HD, Sarbajna S, Matos J, West SC.; ''Coordinated actions of SLX1-SLX4 and MUS81-EME1 for Holliday junction resolution in human cells.''; PubMed
  58. 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

History

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CompareRevisionActionTimeUserComment
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

Datanodes

View all...
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) Numerous types of DNA damage can occur within a cell due to the endogenous production of oxygen free radicals, normal alkylation reactions, or exposure to exogenous radiations and chemicals. Double-strand breaks (DSBs), one of the most dangerous type of DNA damage along with interstrand crosslinks, are caused by ionizing radiation or certain chemicals such as bleomycin, and occur normally during the processes of DNA replication, meiotic exchange, and V(D)J recombination.

The two most prominent mechanisms for DSB repair are the error-free homologous recombination repair (HRR) pathway and the error-prone nonhomologous end-joining (NHEJ) pathway. The choice of the repair pathway may be determined by whether the DNA region has already replicated and the precise nature of the break. NHEJ functions at all stages of the cell cycle, but plays the predominant role in both the G1 phase and in S-phase regions of DNA that have not yet replicated (Rothkamm et al. 2003). HRR functions primarily in repairing both one-sided DSBs that arise at DNA replication forks and two-sided DSBs arising in S or G2-phase chromatid regions that have replicated. For a recent review, please refer to Ciccia and Elledge 2010.

DNA double-strand break endsR-NUL-75165 (Reactome)
Distorted dsDNAR-NUL-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:ZBTB32ComplexR-HSA-419551 (Reactome)
UbComplexR-HSA-68524 (Reactome)
Unhooked ICL-DNA R-HSA-6786149 (Reactome)
ZBTB32 ProteinQ9Y2Y4 (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:ZBTB32-mediated deubiquitination of FANCD2 (Nijman et al. 2005). ZBTB32 (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:ZBTB32TBarR-HSA-6785732 (Reactome)
USP1:ZBTB32mim-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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