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.<p>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:[http://www.reactome.org/PathwayBrowser/#DIAGRAM=6783310 Reactome].Pathway is converted from Reactome ID: 6783310Reactome version: 61Reactome Author: Matthews, Lisaedcbd2c25c84fe5bdfbbaa82dbaf20Numerous 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.<p>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. f18d53Nucleotide 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.<BR>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.<BR>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.<BR>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.<BR>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).c00cf5d19d78c74a47bd2The 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.e99dc4A 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).db3fccb2ba9dc54In 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). db3fccc54e71The 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). c28fcbcead7cec0e26a7aFANCD2 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).ba3ec2FANCM 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).a9dc54FANCD2 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).<p>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).<p>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).
a26ec0a6ea5ee11cead7cb23ba3e26c28Several 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).<p>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). cd6d6ae9ec17d14f53dbaf20defef3dc8Unhooking 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.<p>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.<p>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).cd6d6ae9ec17d14e04defdc8An 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).eb8The 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).eb8d38c84fe5The 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). bd2The 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).ebdbabATR 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).babad5ebdebac58d7924623813PubMedRegulation of FANCD2 and FANCI monoubiquitination by their interaction and by DNA.Longerich S, Kwon Y, Tsai MS, Hlaing AS, Kupfer GM, Sung P.17412408PubMedIdentification of the FANCI protein, a monoubiquitinated FANCD2 paralog required for DNA repair.Smogorzewska A, Matsuoka S, Vinciguerra P, McDonald ER, Hurov KE, Luo J, Ballif BA, Gygi SP, Hofmann K, D'Andrea AD, Elledge SJ.17938197PubMedUBE2T, the Fanconi anemia core complex, and FANCD2 are recruited independently to chromatin: a basis for the regulation of FANCD2 monoubiquitination.Alpi A, Langevin F, Mosedale G, Machida YJ, Dutta A, Patel KJ.11239454PubMedInteraction of the Fanconi anemia proteins and BRCA1 in a common pathway.Garcia-Higuera I, Taniguchi T, Ganesan S, Meyn MS, Timmers C, Hejna J, Grompe M, D'Andrea AD.23906714PubMedMammalian transcription-coupled excision repair.Vermeulen W, Fousteri M.14729973PubMedQuaternary structure of ATR and effects of ATRIP and replication protein A on its DNA binding and kinase activities.Unsal-Kaçmaz K, Sancar A.19111657PubMedMechanistic insight into site-restricted monoubiquitination of FANCD2 by Ube2t, FANCL, and FANCI.Alpi AF, Pace PE, Babu MM, Patel KJ.20671156PubMedFAN1 acts with FANCI-FANCD2 to promote DNA interstrand cross-link repair.Liu T, Ghosal G, Yuan J, Chen J, Huang J.15572677PubMedDNA cross-link repair protein SNM1A interacts with PIAS1 in nuclear focus formation.Ishiai M, Kimura M, Namikoshi K, Yamazoe M, Yamamoto K, Arakawa H, Agematsu K, Matsushita N, Takeda S, Buerstedde JM, Takata M.20347429PubMedMHF1-MHF2, a histone-fold-containing protein complex, participates in the Fanconi anemia pathway via FANCM.Singh TR, Saro D, Ali AM, Zheng XF, Du CH, Killen MW, Sachpatzidis A, Wahengbam K, Pierce AJ, Xiong Y, Sung P, Meetei AR.24389026PubMedStructure of the human FANCL RING-Ube2T complex reveals determinants of cognate E3-E2 selection.Hodson C, Purkiss A, Miles JA, Walden H.23325218PubMedFanconi anaemia and the repair of Watson and Crick DNA crosslinks.Kottemann MC, Smogorzewska A.18082604PubMedA UAF1-containing multisubunit protein complex regulates the Fanconi anemia pathway.Cohn MA, Kowal P, Yang K, Haas W, Huang TT, Gygi SP, D'Andrea AD.24905007PubMedThe genetic and biochemical basis of FANCD2 monoubiquitination.Rajendra E, Oestergaard VH, Langevin F, Wang M, Dornan GL, Patel KJ, Passmore LA.22396592PubMedFanconi anemia (FA) binding protein FAAP20 stabilizes FA complementation group A (FANCA) and participates in interstrand cross-link repair.Leung JW, Wang Y, Fong KW, Huen MS, Li L, Chen J.12897142PubMedPathways of DNA double-strand break repair during the mammalian cell cycle.Rothkamm K, Krüger I, Thompson LH, Löbrich M.18174376PubMedCell cycle-dependent chromatin loading of the Fanconi anemia core complex by FANCM/FAAP24.Kim JM, Kee Y, Gurtan A, D'Andrea AD.18995829PubMedChromatin recruitment of DNA repair proteins: lessons from the fanconi anemia and double-strand break repair pathways.Cohn MA, D'Andrea AD.20603015PubMedIdentification of KIAA1018/FAN1, a DNA repair nuclease recruited to DNA damage by monoubiquitinated FANCD2.MacKay C, Déclais AC, Lundin C, Agostinho A, Deans AJ, MacArtney TJ, Hofmann K, Gartner A, West SC, Helleday T, Lilley DM, Rouse J.23723247PubMedA novel interplay between the Fanconi anemia core complex and ATR-ATRIP kinase during DNA cross-link repair.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.21764741PubMedStructure of the FANCI-FANCD2 complex: insights into the Fanconi anemia DNA repair pathway.Joo W, Xu G, Persky NS, Smogorzewska A, Rudge DG, Buzovetsky O, Elledge SJ, Pavletich NP.19023283PubMedTranscription-coupled DNA repair: two decades of progress and surprises.Hanawalt PC, Spivak G.16943440PubMedPhosphorylation of FANCD2 on two novel sites is required for mitomycin C resistance.Ho GP, Margossian S, Taniguchi T, D'Andrea AD.20965415PubMedThe DNA damage response: making it safe to play with knives.Ciccia A, Elledge SJ.22258451PubMedATR-ATRIP kinase complex triggers activation of the Fanconi anemia DNA repair pathway.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.25500724PubMedStructural insights into 5' flap DNA unwinding and incision by the human FAN1 dimer.Zhao Q, Xue X, Longerich S, Sung P, Xiong Y.21734703PubMedFancd2 counteracts the toxic effects of naturally produced aldehydes in mice.Langevin F, Crossan GP, Rosado IV, Arends MJ, Patel KJ.19596236PubMedHuman SLX4 is a Holliday junction resolvase subunit that binds multiple DNA repair/recombination endonucleases.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.19561358PubMedFANCI protein binds to DNA and interacts with FANCD2 to recognize branched structures.Yuan F, El Hokayem J, Zhou W, Zhang Y.23698467PubMedATR-dependent phosphorylation of FANCM at serine 1045 is essential for FANCM functions.Singh TR, Ali AM, Paramasivam M, Pradhan A, Wahengbam K, Seidman MM, Meetei AR.16027118PubMedATRIP oligomerization is required for ATR-dependent checkpoint signaling.Ball HL, Cortez D.21701511PubMedDNA interstrand crosslink repair and cancer.Deans AJ, West SC.17768402PubMedEmergence of a DNA-damage response network consisting of Fanconi anaemia and BRCA proteins.Wang W.10583946PubMedQuality control by DNA repair.Lindahl T, Wood RD.17289582PubMedIdentification of FAAP24, a Fanconi anemia core complex protein that interacts with FANCM.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.19589784PubMedFANCI binds branched DNA and is monoubiquitinated by UBE2T-FANCL.Longerich S, San Filippo J, Liu D, Sung P.11900249PubMedHow nucleotide excision repair protects against cancer.Friedberg EC.16916645PubMedUBE2T is the E2 in the Fanconi anemia pathway and undergoes negative autoregulation.Machida YJ, Machida Y, Chen Y, Gurtan AM, Kupfer GM, D'Andrea AD, Dutta A.20603016PubMedDeficiency of FANCD2-associated nuclease KIAA1018/FAN1 sensitizes cells to interstrand crosslinking agents.Kratz K, Schöpf B, Kaden S, Sendoel A, Eberhard R, Lademann C, Cannavó E, Sartori AA, Hengartner MO, Jiricny J.25430771PubMedDNA repair. Mechanism of DNA interstrand cross-link processing by repair nuclease FAN1.Wang R, Persky NS, Yoo B, Ouerfelli O, Smogorzewska A, Elledge SJ, Pavletich NP.22692201PubMedCharacterization of the human SNM1A and SNM1B/Apollo DNA repair exonucleases.Sengerová B, Allerston CK, Abu M, Lee SY, Hartley J, Kiakos K, Schofield CJ, Hartley JA, Gileadi O, McHugh PJ.26048987PubMedDeciphering the BRCA1 Tumor Suppressor Network.Jiang Q, Greenberg RA.20347428PubMedA histone-fold complex and FANCM form a conserved DNA-remodeling complex to maintain genome stability.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.24726325PubMedXPF-ERCC1 acts in Unhooking DNA interstrand crosslinks in cooperation with FANCD2 and FANCP/SLX4.Klein Douwel D, Boonen RA, Long DT, Szypowska AA, Räschle M, Walter JC, Knipscheer P.22510687PubMedThe structure of the FANCM-MHF complex reveals physical features for functional assembly.Tao Y, Jin C, Li X, Qi S, Chu L, Niu L, Yao X, Teng M.19995904PubMedDNA polymerase POLN participates in cross-link repair and homologous recombination.Moldovan GL, Madhavan MV, Mirchandani KD, McCaffrey RM, Vinciguerra P, D'Andrea AD.20102227PubMedNovel enzymatic function of DNA polymerase nu in translesion DNA synthesis past major groove DNA-peptide and DNA-DNA cross-links.Yamanaka K, Minko IG, Takata K, Kolbanovskiy A, Kozekov ID, Wood RD, Rizzo CJ, Lloyd RS.20670894PubMedThe FANCM/FAAP24 complex is required for the DNA interstrand crosslink-induced checkpoint response.Huang M, Kim JM, Shiotani B, Yang K, Zou L, D'Andrea AD.21464321PubMedInvolvement of SLX4 in interstrand cross-link repair is regulated by the Fanconi anemia pathway.Yamamoto KN, Kobayashi S, Tsuda M, Kurumizaka H, Takata M, Kono K, Jiricny J, Takeda S, Hirota K.24954209PubMedUnderstanding nucleotide excision repair and its roles in cancer and ageing.Marteijn JA, Lans H, Vermeulen W, Hoeijmakers JH.20603073PubMedA genetic screen identifies FAN1, a Fanconi anemia-associated nuclease necessary for DNA interstrand crosslink repair.Smogorzewska A, Desetty R, Saito TT, Schlabach M, Lach FP, Sowa ME, Clark AB, Kunkel TA, Harper JW, Colaiácovo MP, Elledge SJ.14599765PubMedMechanisms of human DNA repair: an update.Christmann M, Tomicic MT, Roos WP, Kaina B.17460694PubMedFANCI is a second monoubiquitinated member of the Fanconi anemia pathway.Sims AE, Spiteri E, Sims RJ, Arita AG, Lach FP, Landers T, Wurm M, Freund M, Neveling K, Hanenberg H, Auerbach AD, Huang TT.20385554PubMedRAD18-dependent recruitment of SNM1A to DNA repair complexes by a ubiquitin-binding zinc finger.Yang K, Moldovan GL, D'Andrea AD.25099582PubMedPALB2 mutations and breast-cancer risk.Evans MK, Longo DL.22287633PubMedDNA robustly stimulates FANCD2 monoubiquitylation in the complex with FANCI.Sato K, Toda K, Ishiai M, Takata M, Kurumizaka H.24076221PubMedCoordinated actions of SLX1-SLX4 and MUS81-EME1 for Holliday junction resolution in human cells.Wyatt HD, Sarbajna S, Matos J, West SC.18931676PubMedFANCI phosphorylation functions as a molecular switch to turn on the Fanconi anemia pathway.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.DNA repair pathwayPW:0000099Pathway OntologyFanconi's anemiaDOID:13636Diseasedisease pathwayPW:0000013Pathway Ontology