Abstract
Fanconi anemia is a genetic disorder that is characterized by bone marrow failure, as well as a predisposition to malignancies including leukemia and squamous cell carcinoma (SCC). At least 22 genes are associated with Fanconi anemia, constituting the Fanconi anemia DNA repair pathway. This pathway coordinates multiple processes and proteins to facilitate the repair of DNA adducts including interstrand crosslinks (ICLs) that are generated by environmental carcinogens, chemotherapeutic crosslinkers, and metabolic products of alcohol. ICLs can interfere with DNA transactions, including replication and transcription. If not properly removed and repaired, ICLs cause DNA breaks and lead to genomic instability, a hallmark of cancer. In this review, we will discuss the genetic and phenotypic characteristics of Fanconi anemia, the epidemiology of the disease, and associated cancer risk. The sources of ICLs and the role of ICL-inducing chemotherapeutic agents will also be discussed. Finally, we will review the detailed mechanisms of ICL repair via the Fanconi anemia DNA repair pathway, highlighting critical regulatory processes. Together, the information in this review will underscore important contributions to Fanconi anemia research in the past two decades.
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Adamo A, Collis SJ, Adelman CA, Silva N, Horejsi Z, Ward JD, Martinez-Perez E, Boulton SJ, La Volpe A (2010) Preventing nonhomologous end joining suppresses DNA repair defects of Fanconi anemia. Mol Cell 39:25–35. https://doi.org/10.1016/j.molcel.2010.06.026
Al Abo M, Dejsuphong D, Hirota K, Yonetani Y, Yamazoe M, Kurumizaka H, Takeda S (2014) Compensatory functions and interdependency of the DNA-binding domain of BRCA2 with the BRCA1-PALB2-BRCA2 complex. Cancer Res 74:797–807. https://doi.org/10.1158/0008-5472.CAN-13-1443
Alcón P, Shakeel S, Chen ZA, Rappsilber J, Patel KJ, Passmore LA (2020) FANCD2-FANCI is a clamp stabilized on DNA by monoubiquitination of FANCD2 during DNA repair. Nat Struct Mol Biol 27:240–248. https://doi.org/10.1038/s41594-020-0380-1
Alpi AF, Pace PE, Babu MM, Patel KJ (2008) Mechanistic insight into site-restricted monoubiquitination of FANCD2 by Ube2t, FANCL, and FANCI. Mol Cell 32:767–777. https://doi.org/10.1016/j.molcel.2008.12.003
Alter BP (2003) Cancer in Fanconi anemia, 1927–2001. Cancer 97:425–440. https://doi.org/10.1002/cncr.11046
Alter BP (2005) Fanconi’s anemia, transplantation, and cancer. Pediatr Transplant 9(Suppl 7):81–86. https://doi.org/10.1111/j.1399-3046.2005.00440.x
Alter BP (2014) Fanconi anemia and the development of leukemia. Best Pract Res Clin Haematol 27:214–221. https://doi.org/10.1016/j.beha.2014.10.002
Alter BP, Giri N (2016) Thinking of VACTERL-H? Rule out Fanconi anemia according to PHENOS. Am J Med Genet A 170:1520–1524. https://doi.org/10.1002/ajmg.a.37637
Alter BP, Rosenberg PS (2013) VACTERL-H association and Fanconi anemia. Mol Syndromol 4:87–93. https://doi.org/10.1159/000346035
Alter BP, Greene MH, Velazquez I, Rosenberg PS (2003) Cancer in Fanconi anemia. Blood 101:2072. https://doi.org/10.1182/blood-2002-11-3597
Alter BP, Giri N, Savage SA, Quint WG, de Koning MN, Schiffman M (2013) Squamous cell carcinomas in patients with Fanconi anemia and dyskeratosis congenita: a search for human papillomavirus. Int J Cancer 133:1513–1515. https://doi.org/10.1002/ijc.28157
Ameziane N, May P, Haitjema A, van de Vrugt HJ, van Rossum-Fikkert SE, Ristic D, Williams GJ, Balk J, Rockx D, Li H, Rooimans MA, Oostra AB, Velleuer E, Dietrich R, Bleijerveld OB, Maarten Altelaar AF, Meijers-Heijboer H, Joenje H, Glusman G, Roach J, Hood L, Galas D, Wyman C, Balling R, den Dunnen J, de Winter JP, Kanaar R, Gelinas R, Dorsman JC (2015) A novel Fanconi anaemia subtype associated with a dominant-negative mutation in RAD51. Nat Commun 6:8829. https://doi.org/10.1038/ncomms9829
Amunugama R, Willcox S, Wu RA, Abdullah UB, El-Sagheer AH, Brown T, McHugh PJ, Griffith JD, Walter JC (2018) Replication fork reversal during DNA interstrand crosslink repair requires CMG unloading. Cell Rep 23:3419–3428. https://doi.org/10.1016/j.celrep.2018.05.061
Anandarajan V, Noguchi C, Oleksak J, Grothusen G, Terlecky D, Noguchi E (2020) Genetic investigation of formaldehyde-induced DNA damage response in Schizosaccharomyces pombe. Curr Genet 66:593–605. https://doi.org/10.1007/s00294-020-01057-z
Auerbach AD (1995) Fanconi anemia. Dermatol Clin 13:41–49
Auerbach AD (1997) Fanconi anemia: genetic testing in Ashkenazi Jews. Genet Test 1:27–33. https://doi.org/10.1089/gte.1997.1.27
Auerbach AD (2003) Diagnosis of fanconi anemia by diepoxybutane analysis. Curr Protoc Hum Genet. https://doi.org/10.1002/0471142905.hg0807s37
Auerbach AD (2009) Fanconi anemia and its diagnosis. Mutat Res 668:4–10. https://doi.org/10.1016/j.mrfmmm.2009.01.013
Auerbach AD (2015) Diagnosis of Fanconi anemia by diepoxybutane analysis. Curr Protoc Hum Genet 85:8.7.1-8.7.17. https://doi.org/10.1002/0471142905.hg0807s85
Auerbach AD, Allen RG (1991) Leukemia and preleukemia in Fanconi anemia patients. A review of the literature and report of the International Fanconi anemia registry. Cancer Genet Cytogenet 51:1–12. https://doi.org/10.1016/0165-4608(91)90002-c
Auerbach AD, Schroeder TM (1982) First announcement of the Fanconi anemia international registry. Blood 60:1054
Authority EFS (2014) Endogenous formaldehyde turnover in humans compared with exogenous contribution from food sources. EFSA J 12:3550. https://doi.org/10.2903/j.efsa.2014.3550
Awate S, Sommers JA, Datta A, Nayak S, Bellani MA, Yang O, Dunn CA, Nicolae CM, Moldovan GL, Seidman MM, Cantor SB, Brosh RM (2020) FANCJ compensates for RAP80 deficiency and suppresses genomic instability induced by interstrand cross-links. Nucleic Acids Res 48:9161–9180. https://doi.org/10.1093/nar/gkaa660
Beckham TH, Leeman J, Jillian Tsai C, Riaz N, Sherman E, Singh B, Lee N, McBride S, Higginson DS (2019) Treatment modalities and outcomes of Fanconi anemia patients with head and neck squamous cell carcinoma: series of 9 cases and review of the literature. Head Neck 41:1418–1426. https://doi.org/10.1002/hed.25577
Benajiba L, Salvado C, Dalle JH, Jubert C, Galambrun C, Soulier J, Socie G, Peffault de Latour R (2015) HLA-matched related-donor HSCT in Fanconi anemia patients conditioned with cyclophosphamide and fludarabine. Blood 125:417–418. https://doi.org/10.1182/blood-2014-10-605113
Benitez A, Liu W, Palovcak A, Wang G, Moon J, An K, Kim A, Zheng K, Zhang Y, Bai F, Mazin AV, Pei XH, Yuan F, Zhang Y (2018) FANCA promotes DNA double-strand break repair by catalyzing single-strand annealing and strand exchange. Mol Cell 71:621-628.e4. https://doi.org/10.1016/j.molcel.2018.06.030
Berger R, Le Coniat M, Gendron MC (1993) Fanconi anemia. Chromosome breakage and cell cycle studies. Cancer Genet Cytogenet 69:13–16. https://doi.org/10.1016/0165-4608(93)90104-t
Bergstralh DT, Sekelsky J (2008) Interstrand crosslink repair: can XPF-ERCC1 be let off the hook? Trends Genet 24:70–76. https://doi.org/10.1016/j.tig.2007.11.003
Bhat KP, Cortez D (2018) RPA and RAD51: fork reversal, fork protection, and genome stability. Nat Struct Mol Biol 25:446–453. https://doi.org/10.1038/s41594-018-0075-z
Bierings M, Bonfim C, Peffault De Latour R, Aljurf M, Mehta PA, Knol C, Boulad F, Tbakhi A, Esquirol A, McQuaker G, Sucak GA, Othman TB, Halkes CJM, Carpenter B, Niederwieser D, Zecca M, Kroger N, Michallet M, Risitano AM, Ehninger G, Porcher R, Dufour C, Ebmt Saa WP (2018) Transplant results in adults with Fanconi anaemia. Br J Haematol 180:100–109. https://doi.org/10.1111/bjh.15006
Blackford AN, Schwab RA, Nieminuszczy J, Deans AJ, West SC, Niedzwiedz W (2012) The DNA translocase activity of FANCM protects stalled replication forks. Hum Mol Genet 21:2005–2016. https://doi.org/10.1093/hmg/dds013
Bogliolo M, Surralles J (2015) Fanconi anemia: a model disease for studies on human genetics and advanced therapeutics. Curr Opin Genet Dev 33:32–40. https://doi.org/10.1016/j.gde.2015.07.002
Bonfim C, Nichele S, Loth G, Funke VAM, Nabhan SK, Pillonetto DV, Lima ACM, Pasquini R (2022) Transplantation for Fanconi anaemia: lessons learned from Brazil. Lancet Haematol 9:e228–e236. https://doi.org/10.1016/s2352-3026(22)00032-1
Brooks PJ, Zakhari S (2014) Acetaldehyde and the genome: beyond nuclear DNA adducts and carcinogenesis. Environ Mol Mutagen 55:77–91. https://doi.org/10.1002/em.21824
Brosh RM Jr, Bellani M, Liu Y, Seidman MM (2017) Fanconi anemia: A DNA repair disorder characterized by accelerated decline of the hematopoietic stem cell compartment and other features of aging. Ageing Res Rev 33:67–75. https://doi.org/10.1016/j.arr.2016.05.005
Budzowska M, Graham TG, Sobeck A, Waga S, Walter JC (2015) Regulation of the Rev1-pol ζ complex during bypass of a DNA interstrand cross-link. EMBO J 34:1971–1985. https://doi.org/10.15252/embj.201490878
Bueren JA, Quintana-Bustamante O, Almarza E, Navarro S, Río P, Segovia JC, Guenechea G (2020) Advances in the gene therapy of monogenic blood cell diseases. Clin Genet 97:89–102. https://doi.org/10.1111/cge.13593
Callen E, Casado JA, Tischkowitz MD, Bueren JA, Creus A, Marcos R, Dasi A, Estella JM, Munoz A, Ortega JJ, de Winter J, Joenje H, Schindler D, Hanenberg H, Hodgson SV, Mathew CG, Surralles J (2005) A common founder mutation in FANCA underlies the world’s highest prevalence of Fanconi anemia in Gypsy families from Spain. Blood 105:1946–1949. https://doi.org/10.1182/blood-2004-07-2588
Cantres-Velez JA, Blaize JL, Vierra DA, Boisvert RA, Garzon JL, Piraino B, Tan W, Deans AJ, Howlett NG (2021) Cyclin-dependent kinase-mediated phosphorylation of FANCD2 promotes mitotic fidelity. Mol Cell Biol 41:e0023421. https://doi.org/10.1128/mcb.00234-21
Carvalho JP, Dias ML, Carvalho FM, Diz DPE, M, Petito JW, (2002) Squamous cell vulvar carcinoma associated with Fanconi’s anemia: a case report. Int J Gynecol Cancer 12:220–222. https://doi.org/10.1046/j.1525-1438.2002.01090.x
Castella M, Pujol R, Callén E, Trujillo JP, Casado JA, Gille H, Lach FP, Auerbach AD, Schindler D, Benítez J, Porto B, Ferro T, Muñoz A, Sevilla J, Madero L, Cela E, Beléndez C, de Heredia CD, Olivé T, de Toledo JS, Badell I, Torrent M, Estella J, Dasí A, Rodríguez-Villa A, Gómez P, Barbot J, Tapia M, Molinés A, Figuera A, Bueren JA, Surrallés J (2011) Origin, functional role, and clinical impact of Fanconi anemia FANCA mutations. Blood 117:3759–3769. https://doi.org/10.1182/blood-2010-08-299917
Ceccaldi R, Liu JC, Amunugama R, Hajdu I, Primack B, Petalcorin MI, O’Connor KW, Konstantinopoulos PA, Elledge SJ, Boulton SJ, Yusufzai T, D’Andrea AD (2015) Homologous-recombination-deficient tumours are dependent on Polθ-mediated repair. Nature 518:258–262. https://doi.org/10.1038/nature14184
Cejka P, Symington LS (2021) DNA end resection: mechanism and control. Annu Rev Genet 55:285–307. https://doi.org/10.1146/annurev-genet-071719-020312
Chaudhury S, Auerbach AD, Kernan NA, Small TN, Prockop SE, Scaradavou A, Heller G, Wolden S, O’Reilly RJ, Boulad F (2008) Fludarabine-based cytoreductive regimen and T-cell-depleted grafts from alternative donors for the treatment of high-risk patients with Fanconi anaemia. Br J Haematol 140:644–655. https://doi.org/10.1111/j.1365-2141.2007.06975.x
Chaudhury I, Sareen A, Raghunandan M, Sobeck A (2013) FANCD2 regulates BLM complex functions independently of FANCI to promote replication fork recovery. Nucleic Acids Res 41:6444–6459. https://doi.org/10.1093/nar/gkt348
Cheung RS, Castella M, Abeyta A, Gafken PR, Tucker N, Taniguchi T (2017) Ubiquitination-linked phosphorylation of the FANCI S/TQ cluster contributes to activation of the Fanconi anemia I/D2 complex. Cell Rep 19:2432–2440. https://doi.org/10.1016/j.celrep.2017.05.081
Chun MJ, Kim S, Hwang SK, Kim BS, Kim HG, Choi HI, Kim JH, Goh SH, Lee CH (2016) AMP-activated protein kinase is involved in the activation of the Fanconi anemia/BRCA pathway in response to DNA interstrand crosslinks. Oncotarget 7:53642–53653. https://doi.org/10.18632/oncotarget.10686
Ciccia A, Ling C, Coulthard R, Yan Z, Xue Y, Meetei AR, el Laghmani H, Joenje H, McDonald N, de Winter JP, Wang W, West SC (2007) Identification of FAAP24, a Fanconi anemia core complex protein that interacts with FANCM. Mol Cell 25:331–343. https://doi.org/10.1016/j.molcel.2007.01.003
Clauson C, Scharer OD, Niedernhofer L (2013) Advances in understanding the complex mechanisms of DNA interstrand cross-link repair. Cold Spring Harb Perspect Biol 5:a012732. https://doi.org/10.1101/cshperspect.a012732
Cohn MA, Kowal P, Yang K, Haas W, Huang TT, Gygi SP, D’Andrea AD (2007) A UAF1-containing multisubunit protein complex regulates the Fanconi anemia pathway. Mol Cell 28:786–797. https://doi.org/10.1016/j.molcel.2007.09.031
Collins NB, Wilson JB, Bush T, Thomashevski A, Roberts KJ, Jones NJ, Kupfer GM (2009) ATR-dependent phosphorylation of FANCA on serine 1449 after DNA damage is important for FA pathway function. Blood 113:2181–2190. https://doi.org/10.1182/blood-2008-05-154294
Collis SJ, Ciccia A, Deans AJ, Horejsi Z, Martin JS, Maslen SL, Skehel JM, Elledge SJ, West SC, Boulton SJ (2008) FANCM and FAAP24 function in ATR-mediated checkpoint signaling independently of the Fanconi anemia core complex. Mol Cell 32:313–324. https://doi.org/10.1016/j.molcel.2008.10.014
Constantinou A (2012) Rescue of replication failure by Fanconi anaemia proteins. Chromosoma 121:21–36. https://doi.org/10.1007/s00412-011-0349-2
Dao KH, Rotelli MD, Brown BR, Yates JE, Rantala J, Tognon C, Tyner JW, Druker BJ, Bagby GC (2013) The PI3K/Akt1 pathway enhances steady-state levels of FANCL. Mol Biol Cell 24:2582–2592. https://doi.org/10.1091/mbc.E13-03-0144
Datta A, Brosh RM Jr (2019) Holding all the cards-how Fanconi anemia proteins deal with replication stress and preserve genomic stability. Genes (Basel). https://doi.org/10.3390/genes10020170
de Vries Y, Lwiwski N, Levitus M, Kuyt B, Israels SJ, Arwert F, Zwaan M, Greenberg CR, Alter BP, Joenje H, Meijers-Heijboer H (2012) A Dutch Fanconi anemia FANCC founder mutation in Canadian Manitoba Mennonites. Anemia 2012:865170. https://doi.org/10.1155/2012/865170
Deans AJ, West SC (2009) FANCM connects the genome instability disorders Bloom’s Syndrome and Fanconi anemia. Mol Cell 36:943–953. https://doi.org/10.1016/j.molcel.2009.12.006
Demuth I, Wlodarski M, Tipping AJ, Morgan NV, de Winter JP, Thiel M, Gräsl S, Schindler D, D’Andrea AD, Altay C, Kayserili H, Zatterale A, Kunze J, Ebell W, Mathew CG, Joenje H, Sperling K, Digweed M (2000) Spectrum of mutations in the Fanconi anaemia group G gene, FANCG/XRCC9. Eur J Hum Genet 8:861–868. https://doi.org/10.1038/sj.ejhg.5200552
Densham RM, Morris JR (2019) Moving mountains-the BRCA1 promotion of DNA resection. Front Mol Biosci 6:79. https://doi.org/10.3389/fmolb.2019.00079
Dingler FA, Wang M, Mu A, Millington CL, Oberbeck N, Watcham S, Pontel LB, Kamimae-Lanning AN, Langevin F, Nadler C, Cordell RL, Monks PS, Yu R, Wilson NK, Hira A, Yoshida K, Mori M, Okamoto Y, Okuno Y, Muramatsu H, Shiraishi Y, Kobayashi M, Moriguchi T, Osumi T, Kato M, Miyano S, Ito E, Kojima S, Yabe H, Yabe M, Matsuo K, Ogawa S, Göttgens B, Hodskinson MRG, Takata M, Patel KJ (2020) Two aldehyde clearance systems are essential to prevent lethal formaldehyde accumulation in mice and humans. Mol Cell 80:996-1012.e9. https://doi.org/10.1016/j.molcel.2020.10.012
Dubois EL, Guitton-Sert L, Beliveau M, Parmar K, Chagraoui J, Vignard J, Pauty J, Caron MC, Coulombe Y, Buisson R, Jacquet K, Gamblin C, Gao Y, Laprise P, Lebel M, Sauvageau G, DdA A, Masson JY (2019) A Fanci knockout mouse model reveals common and distinct functions for FANCI and FANCD2. Nucleic Acids Res 47:7532–7547. https://doi.org/10.1093/nar/gkz514
Dufour C (2017) How I manage patients with Fanconi anaemia. Br J Haematol 178:32–47. https://doi.org/10.1111/bjh.14615
Duquette ML, Zhu Q, Taylor ER, Tsay AJ, Shi LZ, Berns MW, McGowan CH (2012) CtIP is required to initiate replication-dependent interstrand crosslink repair. PLoS Genet 8:e1003050. https://doi.org/10.1371/journal.pgen.1003050
Dutta S, Chowdhury G, Gates KS (2007) Interstrand cross-links generated by abasic sites in duplex DNA. J Am Chem Soc 129:1852–1853. https://doi.org/10.1021/ja067294u
Duxin JP, Walter JC (2015) What is the DNA repair defect underlying Fanconi anemia? Curr Opin Cell Biol 37:49–60. https://doi.org/10.1016/j.ceb.2015.09.002
Eccles LJ, Bell AC, Powell SN (2018) Inhibition of non-homologous end joining in Fanconi anemia cells results in rescue of survival after interstrand crosslinks but sensitization to replication associated double-strand breaks. DNA Repair (Amst) 64:1–9. https://doi.org/10.1016/j.dnarep.2018.02.003
Fanconi G (1964) Hypothesis of chromosomal translocation as a genetic interpretation of Fanconi’s familial constitutional panmyelopathy. Helv Paediatr Acta 19:29–33
Fanconi G (1967) Herediatary anemia, expecially constitutional familial pancytopathy. Bull Acad Natl Med 151:176–182
Feben C, Kromberg J, Wainwright R, Stones D, Sutton C, Poole J, Haw T, Krause A (2014) Phenotypic consequences in black South African Fanconi anemia patients homozygous for a founder mutation. Genet Med 16:400–406. https://doi.org/10.1038/gim.2013.159
Feben C, Kromberg J, Wainwright R, Stones D, Poole J, Haw T, Krause A (2015) Hematological consequences of a FANCG founder mutation in black South African patients with Fanconi anemia. Blood Cells Mol Dis 54:270–274. https://doi.org/10.1016/j.bcmd.2014.11.011
Feben C, Haw T, Stones D, Jacobs C, Sutton C, Kromberg J, Krause A (2017) Fanconi anaemia in South African patients with afrikaner ancestry. S Afr J Child Health. https://doi.org/10.7196/SAJCH.2017.v11i3.1312
Fiesco-Roa MO, Giri N, McReynolds LJ, Best AF, Alter BP (2019) Genotype-phenotype associations in Fanconi anemia: a literature review. Blood Rev 37:100589. https://doi.org/10.1016/j.blre.2019.100589
Forlenza GP, Polgreen LE, Miller BS, MacMillan ML, Wagner JE, Petryk A (2014) Growth hormone treatment of patients with Fanconi anemia after hematopoietic cell transplantation. Pediatr Blood Cancer 61:1142–1143. https://doi.org/10.1002/pbc.24910
Francies FZ, Wainwright R, Poole J, De Leeneer K, Coene I, Wieme G, Poirel HA, Brichard B, Vermeulen S, Vral A, Slabbert J, Claes K, Baeyens A (2018) Diagnosis of Fanconi anaemia by ionising radiation- or mitomycin C-induced micronuclei. DNA Repair (Amst) 61:17–24. https://doi.org/10.1016/j.dnarep.2017.11.001
Fu D, Dudimah FD, Zhang J, Pickering A, Paneerselvam J, Palrasu M, Wang H, Fei P (2013) Recruitment of DNA polymerase eta by FANCD2 in the early response to DNA damage. Cell Cycle 12:803–809. https://doi.org/10.4161/cc.23755
Fullbright G, Rycenga HB, Gruber JD, Long DT (2016) p97 promotes a conserved mechanism of helicase unloading during DNA cross-link repair. Mol Cell Biol 36:2983–2994. https://doi.org/10.1128/mcb.00434-16
Futaki M, Yamashita T, Yagasaki H, Toda T, Yabe M, Kato S, Asano S, Nakahata T (2000) The IVS4 + 4 A to T mutation of the fanconi anemia gene FANCC is not associated with a severe phenotype in Japanese patients. Blood 95:1493–1498
Garaycoechea JI, Crossan GP, Langevin F, Daly M, Arends MJ, Patel KJ (2012) Genotoxic consequences of endogenous aldehydes on mouse haematopoietic stem cell function. Nature 489:571–575. https://doi.org/10.1038/nature11368
Garg P, Stith CM, Sabouri N, Johansson E, Burgers PM (2004) Idling by DNA polymerase delta maintains a ligatable nick during lagging-strand DNA replication. Genes Dev 18:2764–2773. https://doi.org/10.1101/gad.1252304
Gari K, Décaillet C, Delannoy M, Wu L, Constantinou A (2008a) Remodeling of DNA replication structures by the branch point translocase FANCM. Proc Natl Acad Sci USA 105:16107–16112. https://doi.org/10.1073/pnas.0804777105
Gari K, Décaillet C, Stasiak AZ, Stasiak A, Constantinou A (2008b) The Fanconi anemia protein FANCM can promote branch migration of Holliday junctions and replication forks. Mol Cell 29:141–148. https://doi.org/10.1016/j.molcel.2007.11.032
Gillio AP, Verlander PC, Batish SD, Giampietro PF, Auerbach AD (1997) Phenotypic consequences of mutations in the Fanconi anemia FAC gene: an International Fanconi anemia registry study. Blood 90:105–110
Gruenert DC, Cleaver JE (1985) Repair of psoralen-induced cross-links and monoadducts in normal and repair-deficient human fibroblasts. Cancer Res 45:5399–5404
Guainazzi A, Scharer OD (2010) Using synthetic DNA interstrand crosslinks to elucidate repair pathways and identify new therapeutic targets for cancer chemotherapy. Cell Mol Life Sci 67:3683–3697. https://doi.org/10.1007/s00018-010-0492-6
Guo C, Fischhaber PL, Luk-Paszyc MJ, Masuda Y, Zhou J, Kamiya K, Kisker C, Friedberg EC (2003) Mouse Rev1 protein interacts with multiple DNA polymerases involved in translesion DNA synthesis. EMBO J 22:6621–6630. https://doi.org/10.1093/emboj/cdg626
Gupta R, Sharma S, Sommers JA, Kenny MK, Cantor SB, Brosh RM Jr (2007) FANCJ (BACH1) helicase forms DNA damage inducible foci with replication protein A and interacts physically and functionally with the single-stranded DNA-binding protein. Blood 110:2390–2398. https://doi.org/10.1182/blood-2006-11-057273
Hira A, Yabe H, Yoshida K, Okuno Y, Shiraishi Y, Chiba K, Tanaka H, Miyano S, Nakamura J, Kojima S, Ogawa S, Matsuo K, Takata M, Yabe M (2013) Variant ALDH2 is associated with accelerated progression of bone marrow failure in Japanese Fanconi anemia patients. Blood 122:3206–3209. https://doi.org/10.1182/blood-2013-06-507962
Ho TV, Schärer OD (2010) Translesion DNA synthesis polymerases in DNA interstrand crosslink repair. Environ Mol Mutagen 51:552–566. https://doi.org/10.1002/em.20573
Ho GP, Margossian S, Taniguchi T, D’Andrea AD (2006) Phosphorylation of FANCD2 on two novel sites is required for mitomycin C resistance. Mol Cell Biol 26:7005–7015. https://doi.org/10.1128/mcb.02018-05
Hodskinson MR, Silhan J, Crossan GP, Garaycoechea JI, Mukherjee S, Johnson CM, Schärer OD, Patel KJ (2014) Mouse SLX4 is a tumor suppressor that stimulates the activity of the nuclease XPF-ERCC1 in DNA crosslink repair. Mol Cell 54:472–484. https://doi.org/10.1016/j.molcel.2014.03.014
Hoffmann RF, Moshkin YM, Mouton S, Grzeschik NA, Kalicharan RD, Kuipers J, Wolters AH, Nishida K, Romashchenko AV, Postberg J, Lipps H, Berezikov E, Sibon OC, Giepmans BN, Lansdorp PM (2016) Guanine quadruplex structures localize to heterochromatin. Nucleic Acids Res 44:152–163. https://doi.org/10.1093/nar/gkv900
Hoogenboom WS, Boonen R, Knipscheer P (2019) The role of SLX4 and its associated nucleases in DNA interstrand crosslink repair. Nucleic Acids Res 47:2377–2388. https://doi.org/10.1093/nar/gky1276
Howlett NG, Taniguchi T, Durkin SG, D’Andrea AD, Glover TW (2005) The Fanconi anemia pathway is required for the DNA replication stress response and for the regulation of common fragile site stability. Hum Mol Genet 14:693–701. https://doi.org/10.1093/hmg/ddi065
Huang M, Kim JM, Shiotani B, Yang K, Zou L, D’Andrea AD (2010) The FANCM/FAAP24 complex is required for the DNA interstrand crosslink-induced checkpoint response. Mol Cell 39:259–268. https://doi.org/10.1016/j.molcel.2010.07.005
Huang J, Liu S, Bellani MA, Thazhathveetil AK, Ling C, de Winter JP, Wang Y, Wang W, Seidman MM (2013) The DNA translocase FANCM/MHF promotes replication traverse of DNA interstrand crosslinks. Mol Cell 52:434–446. https://doi.org/10.1016/j.molcel.2013.09.021
Huang Y, Leung JW, Lowery M, Matsushita N, Wang Y, Shen X, Huong D, Takata M, Chen J, Li L (2014) Modularized functions of the Fanconi anemia core complex. Cell Rep 7:1849–1857. https://doi.org/10.1016/j.celrep.2014.04.029
Huang J, Zhang J, Bellani MA, Pokharel D, Gichimu J, James RC, Gali H, Ling C, Yan Z, Xu D, Chen J, Meetei AR, Li L, Wang W, Seidman MM (2019) Remodeling of Interstrand crosslink proximal replisomes is dependent on ATR, FANCM, and FANCD2. Cell Rep 27:1794-1808.e5. https://doi.org/10.1016/j.celrep.2019.04.032
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 (2008) FANCI phosphorylation functions as a molecular switch to turn on the Fanconi anemia pathway. Nat Struct Mol Biol 15:1138–1146. https://doi.org/10.1038/nsmb.1504
Iyama T, Wilson DM 3rd (2013) DNA repair mechanisms in dividing and non-dividing cells. DNA Repair (Amst) 12:620–636. https://doi.org/10.1016/j.dnarep.2013.04.015
Kawanishi M, Matsuda T, Yagi T (2014) Genotoxicity of formaldehyde: molecular basis of DNA damage and mutation. Front Environ Sci. https://doi.org/10.3389/fenvs.2014.00036
Kee Y, D’Andrea AD (2012) Molecular pathogenesis and clinical management of Fanconi anemia. J Clin Invest 122:3799–3806. https://doi.org/10.1172/JCI58321
Kee Y, Kim JM, D’Andrea AD (2009) Regulated degradation of FANCM in the Fanconi anemia pathway during mitosis. Genes Dev 23:555–560. https://doi.org/10.1101/gad.1761309
Kim JM, Kee Y, Gurtan A, D’Andrea AD (2008) Cell cycle-dependent chromatin loading of the Fanconi anemia core complex by FANCM/FAAP24. Blood 111:5215–5222. https://doi.org/10.1182/blood-2007-09-113092
Kim JM, Parmar K, Huang M, Weinstock DM, Ruit CA, Kutok JL, D’Andrea AD (2009) Inactivation of murine Usp1 results in genomic instability and a Fanconi anemia phenotype. Dev Cell 16:314–320. https://doi.org/10.1016/j.devcel.2009.01.001
Kim H, Yang K, Dejsuphong D, D’Andrea AD (2012) Regulation of Rev1 by the Fanconi anemia core complex. Nat Struct Mol Biol 19:164–170. https://doi.org/10.1038/nsmb.2222
Klages-Mundt NL, Li L (2017) Formation and repair of DNA-protein crosslink damage. Sci China Life Sci 60:1065–1076. https://doi.org/10.1007/s11427-017-9183-4
Klein Douwel D, Boonen RA, Long DT, Szypowska AA, Raschle M, Walter JC, Knipscheer P (2014) XPF-ERCC1 acts in Unhooking DNA interstrand crosslinks in cooperation with FANCD2 and FANCP/SLX4. Mol Cell 54:460–471. https://doi.org/10.1016/j.molcel.2014.03.015
Klein Douwel D, Hoogenboom WS, Boonen RA, Knipscheer P (2017) Recruitment and positioning determine the specific role of the XPF-ERCC1 endonuclease in interstrand crosslink repair. EMBO J 36:2034–2046. https://doi.org/10.15252/embj.201695223
Kutler DI, Auerbach AD, Satagopan J, Giampietro PF, Batish SD, Huvos AG, Goberdhan A, Shah JP, Singh B (2003) High incidence of head and neck squamous cell carcinoma in patients with Fanconi anemia. Arch Otolaryngol Head Neck Surg 129:106–112. https://doi.org/10.1001/archotol.129.1.106
Kutler DI, Patel KR, Auerbach AD, Kennedy J, Lach FP, Sanborn E, Cohen MA, Kuhel WI, Smogorzewska A (2016) Natural history and management of Fanconi anemia patients with head and neck cancer: a 10-year follow-up. Laryngoscope 126:870–879. https://doi.org/10.1002/lary.25726
Langevin F, Crossan GP, Rosado IV, Arends MJ, Patel KJ (2011) Fancd2 counteracts the toxic effects of naturally produced aldehydes in mice. Nature 475:53–58. https://doi.org/10.1038/nature10192
Le Breton C, Hennion M, Arimondo PB, Hyrien O (2011) Replication-fork stalling and processing at a single psoralen interstrand crosslink in Xenopus egg extracts. PLoS One 6:e18554. https://doi.org/10.1371/journal.pone.0018554
Lee WTC, Yin Y, Morten MJ, Tonzi P, Gwo PP, Odermatt DC, Modesti M, Cantor SB, Gari K, Huang TT, Rothenberg E (2021) Single-molecule imaging reveals replication fork coupled formation of G-quadruplex structures hinders local replication stress signaling. Nat Commun 12:2525. https://doi.org/10.1038/s41467-021-22830-9
Lemonidis K, Arkinson C, Rennie ML, Walden H (2021) Mechanism, specificity, and function of FANCD2-FANCI ubiquitination and deubiquitination. FEBS J. https://doi.org/10.1111/febs.16077
Levitus M, Waisfisz Q, Godthelp BC, de Vries Y, Hussain S, Wiegant WW, Elghalbzouri-Maghrani E, Steltenpool J, Rooimans MA, Pals G, Arwert F, Mathew CG, Zdzienicka MZ, Hiom K, De Winter JP, Joenje H (2005) The DNA helicase BRIP1 is defective in Fanconi anemia complementation group. J Nat Genet 37:934–935. https://doi.org/10.1038/ng1625
Levran O, Attwooll C, Henry RT, Milton KL, Neveling K, Rio P, Batish SD, Kalb R, Velleuer E, Barral S, Ott J, Petrini J, Schindler D, Hanenberg H, Auerbach AD (2005) The BRCA1-interacting helicase BRIP1 is deficient in Fanconi anemia. Nat Genet 37:931–933. https://doi.org/10.1038/ng1624
Li X, Heyer WD (2008) Homologous recombination in DNA repair and DNA damage tolerance. Cell Res 18:99–113. https://doi.org/10.1038/cr.2008.1
Li J, Holzschu DL, Sugiyama T (2013) PCNA is efficiently loaded on the DNA recombination intermediate to modulate polymerase δ, η, and ζ activities. Proc Natl Acad Sci USA 110:7672–7677. https://doi.org/10.1073/pnas.1222241110
Li N, Wang J, Wallace SS, Chen J, Zhou J, D’Andrea AD (2020) Cooperation of the NEIL3 and Fanconi anemia/BRCA pathways in interstrand crosslink repair. Nucleic Acids Res 48:3014–3028. https://doi.org/10.1093/nar/gkaa038
Liang F, Miller AS, Longerich S, Tang C, Maranon D, Williamson EA, Hromas R, Wiese C, Kupfer GM, Sung P (2019) DNA requirement in FANCD2 deubiquitination by USP1-UAF1-RAD51AP1 in the Fanconi anemia DNA damage response. Nat Commun 10:2849. https://doi.org/10.1038/s41467-019-10408-5
Ling C, Huang J, Yan Z, Li Y, Ohzeki M, Ishiai M, Xu D, Takata M, Seidman M, Wang W (2016) Bloom syndrome complex promotes FANCM recruitment to stalled replication forks and facilitates both repair and traverse of DNA interstrand crosslinks. Cell Discov 2:16047. https://doi.org/10.1038/celldisc.2016.47
Litman R, Peng M, Jin Z, Zhang F, Zhang J, Powell S, Andreassen PR, Cantor SB (2005) BACH1 is critical for homologous recombination and appears to be the Fanconi anemia gene product FANCJ. Cancer Cell 8:255–265. https://doi.org/10.1016/j.ccr.2005.08.004
Lobitz S, Velleuer E (2006) Guido Fanconi (1892–1979): a jack of all trades. Nat Rev Cancer 6:893–898. https://doi.org/10.1038/nrc2009
Long DT, Raschle M, Joukov V, Walter JC (2011) Mechanism of RAD51-dependent DNA interstrand cross-link repair. Science 333:84–87. https://doi.org/10.1126/science.1204258
Longerich S, Kwon Y, Tsai MS, Hlaing AS, Kupfer GM, Sung P (2014) Regulation of FANCD2 and FANCI monoubiquitination by their interaction and by DNA. Nucleic Acids Res 42:5657–5670. https://doi.org/10.1093/nar/gku198
Lopez-Martinez D, Liang CC, Cohn MA (2016) Cellular response to DNA interstrand crosslinks: the Fanconi anemia pathway. Cell Mol Life Sci 73:3097–3114. https://doi.org/10.1007/s00018-016-2218-x
Lopez-Martinez D, Kupculak M, Yang D, Yoshikawa Y, Liang CC, Wu R, Gygi SP, Cohn MA (2019) Phosphorylation of FANCD2 inhibits the FANCD2/FANCI complex and suppresses the Fanconi anemia pathway in the absence of DNA damage. Cell Rep 27(2990–3005):e5. https://doi.org/10.1016/j.celrep.2019.05.003
Lossaint G, Larroque M, Ribeyre C, Bec N, Larroque C, Décaillet C, Gari K, Constantinou A (2013) FANCD2 binds MCM proteins and controls replisome function upon activation of s phase checkpoint signaling. Mol Cell 51:678–690. https://doi.org/10.1016/j.molcel.2013.07.023
Lu R, O’Rourke JJ, Sobinoff AP, Allen JAM, Nelson CB, Tomlinson CG, Lee M, Reddel RR, Deans AJ, Pickett HA (2019) The FANCM-BLM-TOP3A-RMI complex suppresses alternative lengthening of telomeres (ALT). Nat Commun 10:2252. https://doi.org/10.1038/s41467-019-10180-6
Lustig JP, Lugassy G, Neder A, Sigler E (1995) Head and neck carcinoma in Fanconi’s anaemia–report of a case and review of the literature. Eur J Cancer B Oral Oncol 31B:68–72. https://doi.org/10.1016/0964-1955(94)00044-5
MacMillan ML, Wagner JE (2010) Haematopoeitic cell transplantation for Fanconi anaemia—when and how? Br J Haematol 149:14–21. https://doi.org/10.1111/j.1365-2141.2010.08078.x
Madjunkova S, Kocheva SA, Plaseska-Karanfilska D (2014) Fanconi anemia founder mutation in Macedonian patients. Acta Haematol 132:15–21. https://doi.org/10.1159/000355191
Magdalena N, Pilonetto DV, Bitencourt MA, Pereira NF, Ribeiro RC, Jeng M, Pasquini R (2005) Frequency of Fanconi anemia in Brazil and efficacy of screening for the FANCA 3788–3790del mutation. Braz J Med Biol Res 38:669–673. https://doi.org/10.1590/s0100-879x2005000500003
Maizels N, Gray LT (2013) The G4 genome. PLoS Genet 9:e1003468. https://doi.org/10.1371/journal.pgen.1003468
Malouf C, Loughran SJ, Wilkinson AC, Shimamura A, Río P (2022) Translational research for bone marrow failure patients. Exp Hematol 105:18–21. https://doi.org/10.1016/j.exphem.2021.11.004
Maric M, Maculins T, De Piccoli G, Labib K (2014) Cdc48 and a ubiquitin ligase drive disassembly of the CMG helicase at the end of DNA replication. Science 346:1253596. https://doi.org/10.1126/science.1253596
Masserot-Lureau C, Adoui N, Degos F, de Bazelaire C, Soulier J, Chevret S, Socie G, Leblanc T (2012) Incidence of liver abnormalities in Fanconi anemia patients. Am J Hematol 87:547–549. https://doi.org/10.1002/ajh.23153
McHugh PJ, Sarkar S (2006) DNA interstrand cross-link repair in the cell cycle: a critical role for polymerase zeta in G1 phase. Cell Cycle 5:1044–1047. https://doi.org/10.4161/cc.5.10.2763
McVey M, Khodaverdian VY, Meyer D, Cerqueira PG, Heyer WD (2016) Eukaryotic DNA polymerases in homologous recombination. Annu Rev Genet 50:393–421. https://doi.org/10.1146/annurev-genet-120215-035243
Meetei AR, Levitus M, Xue Y, Medhurst AL, Zwaan M, Ling C, Rooimans MA, Bier P, Hoatlin M, Pals G, de Winter JP, Wang W, Joenje H (2004) X-linked inheritance of Fanconi anemia complementation group B. Nat Genet 36:1219–1224. https://doi.org/10.1038/ng1458
Meyer S, Fergusson WD, Oostra AB, Medhurst AL, Waisfisz Q, de Winter JP, Chen F, Carr TF, Clayton-Smith J, Clancy T, Green M, Barber L, Eden OB, Will AM, Joenje H, Taylor GM (2005) A cross-linker-sensitive myeloid leukemia cell line from a 2-year-old boy with severe Fanconi anemia and biallelic FANCD1/BRCA2 mutations. Genes Chromosomes Cancer 42:404–415. https://doi.org/10.1002/gcc.20153
Milletti G, Strocchio L, Pagliara D, Girardi K, Carta R, Mastronuzzi A, Locatelli F, Nazio F (2020) Canonical and noncanonical roles of Fanconi anemia proteins: implications in cancer predisposition. Cancers (Basel). https://doi.org/10.3390/cancers12092684
Minko IG, Harbut MB, Kozekov ID, Kozekova A, Jakobs PM, Olson SB, Moses RE, Harris TM, Rizzo CJ, Lloyd RS (2008) Role for DNA polymerase kappa in the processing of N2–N2-guanine interstrand cross-links. J Biol Chem 283:17075–17082. https://doi.org/10.1074/jbc.M801238200
Mitchell R, Wagner JE, Hirsch B, DeFor TE, Zierhut H, MacMillan ML (2014) Haematopoietic cell transplantation for acute leukaemia and advanced myelodysplastic syndrome in Fanconi anaemia. Br J Haematol 164:384–395. https://doi.org/10.1111/bjh.12634
Moreno SP, Bailey R, Campion N, Herron S, Gambus A (2014) Polyubiquitylation drives replisome disassembly at the termination of DNA replication. Science 346:477–481. https://doi.org/10.1126/science.1253585
Mosedale G, Niedzwiedz W, Alpi A, Perrina F, Pereira-Leal JB, Johnson M, Langevin F, Pace P, Patel KJ (2005) The vertebrate Hef ortholog is a component of the Fanconi anemia tumor-suppressor pathway. Nat Struct Mol Biol 12:763–771. https://doi.org/10.1038/nsmb981
Mousavi A, Abbasi F, Abadi AG, Hashemi FA (2010) Vulvar squamous cell carcinoma associated with Fanconi’s anemia. Int J Hematol 91:498–500. https://doi.org/10.1007/s12185-010-0525-9
Murina O, von Aesch C, Karakus U, Ferretti LP, Bolck HA, Hanggi K, Sartori AA (2014) FANCD2 and CtIP cooperate to repair DNA interstrand crosslinks. Cell Rep 7:1030–1038. https://doi.org/10.1016/j.celrep.2014.03.069
Mutreja K, Krietsch J, Hess J, Ursich S, Berti M, Roessler FK, Zellweger R, Patra M, Gasser G, Lopes M (2018) ATR-mediated global fork slowing and reversal assist fork traverse and prevent chromosomal breakage at DNA interstrand cross-links. Cell Rep 24(2629–2642):e5. https://doi.org/10.1016/j.celrep.2018.08.019
Nalepa G, Clapp DW (2018) Fanconi anaemia and cancer: an intricate relationship. Nat Rev Cancer 18:168–185. https://doi.org/10.1038/nrc.2017.116
Nath S, Nagaraju G (2020) FANCJ helicase promotes DNA end resection by facilitating CtIP recruitment to DNA double-strand breaks. PLoS Genet 16:e1008701. https://doi.org/10.1371/journal.pgen.1008701
Nepal M, Che R, Zhang J, Ma C, Fei P (2017) Fanconi anemia signaling and cancer. Trends Cancer 3:840–856. https://doi.org/10.1016/j.trecan.2017.10.005
Nie Y, Li Y, Li X, Wilson AF, Pang Q (2019) The non-homologous end-joining activity is required for Fanconi anemia fetal HSC maintenance. Stem Cell Res Ther 10:114. https://doi.org/10.1186/s13287-019-1206-0
Nijman SM, Huang TT, Dirac AM, Brummelkamp TR, Kerkhoven RM, D’Andrea AD, Bernards R (2005) The deubiquitinating enzyme USP1 regulates the Fanconi anemia pathway. Mol Cell 17:331–339. https://doi.org/10.1016/j.molcel.2005.01.008
Niraj J, Caron MC, Drapeau K, Berube S, Guitton-Sert L, Coulombe Y, Couturier AM, Masson JY (2017) The identification of FANCD2 DNA binding domains reveals nuclear localization sequences. Nucleic Acids Res 45:8341–8357. https://doi.org/10.1093/nar/gkx543
Niraj J, Farkkila A, D’Andrea AD (2019) The Fanconi anemia pathway in cancer. Annu Rev Cancer Biol 3:457–478. https://doi.org/10.1146/annurev-cancerbio-030617-050422
Noguchi C, Grothusen G, Anandarajan V, Martínez-Lage García M, Terlecky D, Corzo K, Tanaka K, Nakagawa H, Noguchi E (2017) Genetic controls of DNA damage avoidance in response to acetaldehyde in fission yeast. Cell Cycle 16:45–58. https://doi.org/10.1080/15384101.2016.1237326
O’Brien PJ, Siraki AG, Shangari N (2005) Aldehyde sources, metabolism, molecular toxicity mechanisms, and possible effects on human health. Crit Rev Toxicol 35:609–662. https://doi.org/10.1080/10408440591002183
Oestergaard VH, Langevin F, Kuiken HJ, Pace P, Niedzwiedz W, Simpson LJ, Ohzeki M, Takata M, Sale JE, Patel KJ (2007) Deubiquitination of FANCD2 is required for DNA crosslink repair. Mol Cell 28:798–809. https://doi.org/10.1016/j.molcel.2007.09.020
Ozenne V, Paradis V, Vullierme MP, Vilgrain V, Leblanc T, Belghiti J, Imbert A, Valla DC, Degos F (2008) Liver tumours in patients with Fanconi anaemia: a report of three cases. Eur J Gastroenterol Hepatol 20:1036–1039. https://doi.org/10.1097/MEG.0b013e3282f824e9
Pace P, Mosedale G, Hodskinson MR, Rosado IV, Sivasubramaniam M, Patel KJ (2010) Ku70 corrupts DNA repair in the absence of the Fanconi anemia pathway. Science 329:219–223. https://doi.org/10.1126/science.1192277
Pagano G, d’Ischia M, Pallardo FV (2015) Fanconi anemia (FA) and crosslinker sensitivity: re-appraising the origins of FA definition. Pediatr Blood Cancer 62:1137–1143. https://doi.org/10.1002/pbc.25452
Pan X, Drosopoulos WC, Sethi L, Madireddy A, Schildkraut CL, Zhang D (2017) FANCM, BRCA1, and BLM cooperatively resolve the replication stress at the ALT telomeres. Proc Natl Acad Sci USA 114:E5940-e5949. https://doi.org/10.1073/pnas.1708065114
Park J, Chung NG, Chae H, Kim M, Lee S, Kim Y, Lee JW, Cho B, Jeong DC, Park IY (2013) FANCA and FANCG are the major Fanconi anemia genes in the Korean population. Clin Genet 84:271–275. https://doi.org/10.1111/cge.12042
Park J, Kim M, Jang W, Chae H, Kim Y, Chung NG, Lee JW, Cho B, Jeong DC, Park IY, Park MS (2015) Founder haplotype analysis of Fanconi anemia in the Korean population finds common ancestral haplotypes for a FANCG variant. Ann Hum Genet 79:153–161. https://doi.org/10.1111/ahg.12097
Pontel LB, Rosado IV, Burgos-Barragan G, Garaycoechea JI, Yu R, Arends MJ, Chandrasekaran G, Broecker V, Wei W, Liu L, Swenberg JA, Crossan GP, Patel KJ (2015) Endogenous formaldehyde is a hematopoietic stem cell genotoxin and metabolic carcinogen. Mol Cell 60:177–188. https://doi.org/10.1016/j.molcel.2015.08.020
Powers KT, Washington MT (2018) Eukaryotic translesion synthesis: choosing the right tool for the job. DNA Repair (Amst) 71:127–134. https://doi.org/10.1016/j.dnarep.2018.08.016
Ragland RL, Patel S, Rivard RS, Smith K, Peters AA, Bielinsky AK, Brown EJ (2013) RNF4 and PLK1 are required for replication fork collapse in ATR-deficient cells. Genes Dev 27:2259–2273. https://doi.org/10.1101/gad.223180.113
Rajendra E, Garaycoechea JI, Patel KJ, Passmore LA (2014a) Abundance of the Fanconi anaemia core complex is regulated by the RuvBL1 and RuvBL2 AAA+ ATPases. Nucleic Acids Res 42:13736–13748. https://doi.org/10.1093/nar/gku1230
Rajendra E, Oestergaard VH, Langevin F, Wang M, Dornan GL, Patel KJ, Passmore LA (2014b) The genetic and biochemical basis of FANCD2 monoubiquitination. Mol Cell 54:858–869. https://doi.org/10.1016/j.molcel.2014.05.001
Rao VB, Kerketta L, Korgaonkar S, Ghosh K (2007) Differentiation of Nijmegen breakage syndrome from Fanconi anemia. Genet Mol Res 6:622–626
Rego MA, Harney JA, Mauro M, Shen M, Howlett NG (2012) Regulation of the activation of the Fanconi anemia pathway by the p21 cyclin-dependent kinase inhibitor. Oncogene 31:366–375. https://doi.org/10.1038/onc.2011.237
Rego MA, Kolling FWT, Vuono EA, Mauro M, Howlett NG (2012) Regulation of the Fanconi anemia pathway by a CUE ubiquitin-binding domain in the FANCD2 protein. Blood 120:2109–17. https://doi.org/10.1182/blood-2012-02-410472
Ren X, Ji Z, McHale CM, Yuh J, Bersonda J, Tang M, Smith MT, Zhang L (2013) The impact of FANCD2 deficiency on formaldehyde-induced toxicity in human lymphoblastoid cell lines. Arch Toxicol 87:189–196. https://doi.org/10.1007/s00204-012-0911-6
Renaudin X, Rosselli F (2020) The FANC/BRCA pathway releases replication blockades by eliminating DNA interstrand cross-links. Genes (Basel). https://doi.org/10.3390/genes11050585
Reyes P, García-de Teresa B, Juárez U, Pérez-Villatoro F, Fiesco-Roa MO, Rodríguez A, Molina B, Villarreal-Molina MT, Meléndez-Zajgla J, Carnevale A, Torres L, Frias S (2022) Fanconi anemia patients from an indigenous community in Mexico carry a new founder pathogenic variant in FANCG. Int J Mol Sci. https://doi.org/10.3390/ijms23042334
Richardson CD, Kazane KR, Feng SJ, Zelin E, Bray NL, Schäfer AJ, Floor SN, Corn JE (2018) CRISPR-Cas9 genome editing in human cells occurs via the Fanconi anemia pathway. Nat Genet 50:1132–1139. https://doi.org/10.1038/s41588-018-0174-0
Río P, Navarro S, Guenechea G, Sánchez-Domínguez R, Lamana ML, Yañez R, Casado JA, Mehta PA, Pujol MR, Surrallés J, Charrier S, Galy A, Segovia JC, Díaz de Heredia C, Sevilla J, Bueren JA (2017) Engraftment and in vivo proliferation advantage of gene-corrected mobilized CD34(+) cells from Fanconi anemia patients. Blood 130:1535–1542. https://doi.org/10.1182/blood-2017-03-774174
Rogers CM, Simmons Iii RH, Fluhler Thornburg GE, Buehler NJ, Bochman ML (2020) Fanconi anemia-independent DNA inter-strand crosslink repair in eukaryotes. Prog Biophys Mol Biol 158:33–46. https://doi.org/10.1016/j.pbiomolbio.2020.08.005
Rohleder F, Huang J, Xue Y, Kuper J, Round A, Seidman M, Wang W, Kisker C (2016) FANCM interacts with PCNA to promote replication traverse of DNA interstrand crosslinks. Nucleic Acids Res 44:3219–3232. https://doi.org/10.1093/nar/gkw037
Román-Rodríguez FJ, Ugalde L, Álvarez L, Díez B, Ramírez MJ, Risueño C, Cortón M, Bogliolo M, Bernal S, March F, Ayuso C, Hanenberg H, Sevilla J, Rodríguez-Perales S, Torres-Ruiz R, Surrallés J, Bueren JA, Río P (2019) NHEJ-mediated repair of CRISPR-Cas9-induced DNA breaks efficiently corrects mutations in HSPCs from patients with Fanconi anemia. Cell Stem Cell 25:607-621.e7. https://doi.org/10.1016/j.stem.2019.08.016
Rosado IV, Niedzwiedz W, Alpi AF, Patel KJ (2009) The Walker B motif in avian FANCM is required to limit sister chromatid exchanges but is dispensable for DNA crosslink repair. Nucleic Acids Res 37:4360–4370. https://doi.org/10.1093/nar/gkp365
Roseaulin LC, Noguchi C, Martinez E, Ziegler MA, Toda T, Noguchi E (2013a) Coordinated degradation of replisome components ensures genome stability upon replication stress in the absence of the replication fork protection complex. PLoS Genet 9:e1003213. https://doi.org/10.1371/journal.pgen.1003213
Roseaulin LC, Noguchi C, Noguchi E (2013b) Proteasome-dependent degradation of replisome components regulates faithful DNA replication. Cell Cycle 12:2564–2569. https://doi.org/10.4161/cc.25692
Rosenberg PS, Greene MH, Alter BP (2003) Cancer incidence in persons with Fanconi anemia. Blood 101:822–826. https://doi.org/10.1182/blood-2002-05-1498
Rosenberg PS, Socie G, Alter BP, Gluckman E (2005) Risk of head and neck squamous cell cancer and death in patients with Fanconi anemia who did and did not receive transplants. Blood 105:67–73. https://doi.org/10.1182/blood-2004-04-1652
Rosenberg PS, Tamary H, Alter BP (2011) How high are carrier frequencies of rare recessive syndromes? Contemporary estimates for Fanconi anemia in the United States and Israel. Am J Med Genet A 155A:1877–1883. https://doi.org/10.1002/ajmg.a.34087
Rosendorff J, Bernstein R, Macdougall L, Jenkins T (1987) Fanconi anemia: another disease of unusually high prevalence in the Afrikaans population of South Africa. Am J Med Genet 27:793–797. https://doi.org/10.1002/ajmg.1320270408
Roy U, Schärer OD (2016) Involvement of translesion synthesis DNA polymerases in DNA interstrand crosslink repair. DNA Repair (Amst) 44:33–41. https://doi.org/10.1016/j.dnarep.2016.05.004
Sale JE, Lehmann AR, Woodgate R (2012) Y-family DNA polymerases and their role in tolerance of cellular DNA damage. Nat Rev Mol Cell Biol 13:141–152. https://doi.org/10.1038/nrm3289
Sarbajna S, West SC (2014) Holliday junction processing enzymes as guardians of genome stability. Trends Biochem Sci 39:409–419. https://doi.org/10.1016/j.tibs.2014.07.003
Sato K, Toda K, Ishiai M, Takata M, Kurumizaka H (2012) DNA robustly stimulates FANCD2 monoubiquitylation in the complex with FANCI. Nucleic Acids Res 40:4553–4561. https://doi.org/10.1093/nar/gks053
Schwab RA, Blackford AN, Niedzwiedz W (2010) ATR activation and replication fork restart are defective in FANCM-deficient cells. EMBO J 29:806–818. https://doi.org/10.1038/emboj.2009.385
Schwab RA, Nieminuszczy J, Shin-ya K, Niedzwiedz W (2013) FANCJ couples replication past natural fork barriers with maintenance of chromatin structure. J Cell Biol 201:33–48. https://doi.org/10.1083/jcb.201208009
Sczepanski JT, Jacobs AC, Greenberg MM (2008) Self-promoted DNA interstrand cross-link formation by an abasic site. J Am Chem Soc 130:9646–9647. https://doi.org/10.1021/ja8030642
Semlow DR, Walter JC (2021) Mechanisms of vertebrate DNA interstrand cross-link repair. Annu Rev Biochem 90:107–135. https://doi.org/10.1146/annurev-biochem-080320-112510
Shapiro R, Dubelman S, Feinberg AM, Crain PF, McCloskey JA (1977) Isolation and identification of cross-linked nucleosides from nitrous acid treated deoxyribonucleic acid. J Am Chem Soc 99:302–303. https://doi.org/10.1021/ja00443a080
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 (2012) ATR-ATRIP kinase complex triggers activation of the Fanconi anemia DNA repair pathway. Cancer Res 72:1149–1156. https://doi.org/10.1158/0008-5472.CAN-11-2904
Shimamura A, Montes de Oca R, Svenson JL, Haining N, Moreau LA, Nathan DG, D’Andrea AD (2002) A novel diagnostic screen for defects in the Fanconi anemia pathway. Blood 100:4649–4654. https://doi.org/10.1182/blood-2002-05-1399
Singh TR, Saro D, Ali AM, Zheng XF, Du CH, Killen MW, Sachpatzidis A, Wahengbam K, Pierce AJ, Xiong Y, Sung P, Meetei AR (2010) MHF1-MHF2, a histone-fold-containing protein complex, participates in the Fanconi anemia pathway via FANCM. Mol Cell 37:879–886. https://doi.org/10.1016/j.molcel.2010.01.036
Singh TR, Ali AM, Paramasivam M, Pradhan A, Wahengbam K, Seidman MM, Meetei AR (2013) ATR-dependent phosphorylation of FANCM at serine 1045 is essential for FANCM functions. Cancer Res 73:4300–4310. https://doi.org/10.1158/0008-5472.CAN-12-3976
Sobeck A, Stone S, Landais I, de Graaf B, Hoatlin ME (2009) The Fanconi anemia protein FANCM is controlled by FANCD2 and the ATR/ATM pathways. J Biol Chem 284:25560–25568. https://doi.org/10.1074/jbc.M109.007690
Stern RS (2007) Psoralen and ultraviolet a light therapy for psoriasis. N Engl J Med 357:682–690. https://doi.org/10.1056/NEJMct072317
Stingele J, Bellelli R, Boulton SJ (2017) Mechanisms of DNA-protein crosslink repair. Nat Rev Mol Cell Biol 18:563–573. https://doi.org/10.1038/nrm.2017.56
Swuec P, Renault L, Borg A, Shah F, Murphy VJ, van Twest S, Snijders AP, Deans AJ, Costa A (2017) The FA core complex contains a homo-dimeric catalytic module for the symmetric mono-ubiquitination of FANCI-FANCD2. Cell Rep 18:611–623. https://doi.org/10.1016/j.celrep.2016.11.013
Takenaka S, Kuroda Y, Ohta S, Mizuno Y, Hiwatari M, Miyatake S, Matsumoto N, Oka A (2019) A Japanese patient with RAD51-associated Fanconi anemia. Am J Med Genet A 179:900–902. https://doi.org/10.1002/ajmg.a.61130
Tamary H, Bar-Yam R, Shalmon L, Rachavi G, Krostichevsky M, Elhasid R, Barak Y, Kapelushnik J, Yaniv I, Auerbach AD, Zaizov R (2000) Fanconi anaemia group A (FANCA) mutations in Israeli non-Ashkenazi Jewish patients. Br J Haematol 111:338–343. https://doi.org/10.1046/j.1365-2141.2000.02323.x
Tamary H, Dgany O, Toledano H, Shalev Z, Krasnov T, Shalmon L, Schechter T, Bercovich D, Attias D, Laor R, Koren A, Yaniv I (2004) Molecular characterization of three novel Fanconi anemia mutations in Israeli Arabs. Eur J Haematol 72:330–335. https://doi.org/10.1111/j.1600-0609.2004.00240.x
Tan W, van Twest S, Murphy VJ, Deans AJ (2020) ATR-Mediated FANCI phosphorylation regulates both ubiquitination and deubiquitination of FANCD2. Front Cell Dev Biol 8:2. https://doi.org/10.3389/fcell.2020.00002
Taniguchi T, Garcia-Higuera I, Xu B, Andreassen PR, Gregory RC, Kim ST, Lane WS, Kastan MB, D’Andrea AD (2002) Convergence of the Fanconi anemia and ataxia telangiectasia signaling pathways. Cell 109:459–472. https://doi.org/10.1016/s0092-8674(02)00747-x
Tipping AJ, Pearson T, Morgan NV, Gibson RA, Kuyt LP, Havenga C, Gluckman E, Joenje H, de Ravel T, Jansen S, Mathew CG (2001) Molecular and genealogical evidence for a founder effect in Fanconi anemia families of the Afrikaner population of South Africa. Proc Natl Acad Sci USA 98:5734–5739. https://doi.org/10.1073/pnas.091402398
Tischkowitz MD, Hodgson SV (2003) Fanconi anaemia. J Med Genet 40:1–10. https://doi.org/10.1136/jmg.40.1.1
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 (2013) A novel interplay between the Fanconi anemia core complex and ATR-ATRIP kinase during DNA cross-link repair. Nucleic Acids Res 41:6930–6941. https://doi.org/10.1093/nar/gkt467
Unno J, Itaya A, Taoka M, Sato K, Tomida J, Sakai W, Sugasawa K, Ishiai M, Ikura T, Isobe T, Kurumizaka H, Takata M (2014) FANCD2 binds CtIP and regulates DNA-end resection during DNA interstrand crosslink repair. Cell Rep 7:1039–1047. https://doi.org/10.1016/j.celrep.2014.04.005
van der Heijden MS, Yeo CJ, Hruban RH, Kern SE (2003) Fanconi anemia gene mutations in young-onset pancreatic cancer. Cancer Res 63:2585–2588
van der Lelij P, Oostra AB, Rooimans MA, Joenje H, de Winter JP (2010) Diagnostic overlap between Fanconi anemia and the cohesinopathies: Roberts syndrome and Warsaw breakage syndrome. Anemia 2010:565268. https://doi.org/10.1155/2010/565268
van Twest S, Murphy VJ, Hodson C, Tan W, Swuec P, O’Rourke JJ, Heierhorst J, Crismani W, Deans AJ (2017) Mechanism of ubiquitination and deubiquitination in the Fanconi anemia pathway. Mol Cell 65:247–259. https://doi.org/10.1016/j.molcel.2016.11.005
Vanni VS, Campo G, Cioffi R, Papaleo E, Salonia A, Viganò P, Lambertini M, Candiani M, Meirow D, Orvieto R (2022) The neglected members of the family: non-BRCA mutations in the Fanconi anemia/BRCA pathway and reproduction. Hum Reprod Update 28:296–311. https://doi.org/10.1093/humupd/dmab045
Velleuer E, Dietrich R (2014) Fanconi anemia: young patients at high risk for squamous cell carcinoma. Mol Cell Pediatr 1:9. https://doi.org/10.1186/s40348-014-0009-8
Wainstein T, Kerr R, Mitchell CL, Madaree S, Essop FB, Vorster E, Wainwright R, Poole J, Krause A (2013) Fanconi anaemia in black South African patients heterozygous for the FANCG c.637-643delTACCGCC founder mutation. S Afr Med J 103:970–973. https://doi.org/10.7196/samj.7215
Wang AT, Smogorzewska A (2015) SnapShot: Fanconi anemia and associated proteins. Cell 160(354–354):e1. https://doi.org/10.1016/j.cell.2014.12.031
Wang X, Kennedy RD, Ray K, Stuckert P, Ellenberger T, D’Andrea AD (2007) Chk1-mediated phosphorylation of FANCE is required for the Fanconi anemia/BRCA pathway. Mol Cell Biol 27:3098–3108. https://doi.org/10.1128/MCB.02357-06
Wang LC, Stone S, Hoatlin ME, Gautier J (2008) Fanconi anemia proteins stabilize replication forks. DNA Repair (Amst) 7:1973–1981. https://doi.org/10.1016/j.dnarep.2008.08.005
Wang AT, Sengerová B, Cattell E, Inagawa T, Hartley JM, Kiakos K, Burgess-Brown NA, Swift LP, Enzlin JH, Schofield CJ, Gileadi O, Hartley JA, McHugh PJ (2011) Human SNM1A and XPF-ERCC1 collaborate to initiate DNA interstrand cross-link repair. Genes Dev 25:1859–1870. https://doi.org/10.1101/gad.15699211
Wang Y, Leung JW, Jiang Y, Lowery MG, Do H, Vasquez KM, Chen J, Wang W, Li L (2013) FANCM and FAAP24 maintain genome stability via cooperative as well as unique functions. Mol Cell 49:997–1009. https://doi.org/10.1016/j.molcel.2012.12.010
Wang R, Wang S, Dhar A, Peralta C, Pavletich NP (2020) DNA clamp function of the monoubiquitinated Fanconi anaemia ID complex. Nature 580:278–282. https://doi.org/10.1038/s41586-020-2110-6
Wang S, Wang R, Peralta C, Yaseen A, Pavletich NP (2021) Structure of the FA core ubiquitin ligase closing the ID clamp on DNA. Nat Struct Mol Biol 28:300–309. https://doi.org/10.1038/s41594-021-00568-8
Wang M, Dingler FA, Patel KJ (2022) Genotoxic aldehydes in the hematopoietic system. Blood. https://doi.org/10.1182/blood.2019004316
Whitney MA, Saito H, Jakobs PM, Gibson RA, Moses RE, Grompe M (1993) A common mutation in the FACC gene causes Fanconi anaemia in Ashkenazi Jews. Nat Genet 4:202–205. https://doi.org/10.1038/ng0693-202
Williams SA, Longerich S, Sung P, Vaziri C, Kupfer GM (2011) The E3 ubiquitin ligase RAD18 regulates ubiquitylation and chromatin loading of FANCD2 and FANCI. Blood 117:5078–5087. https://doi.org/10.1182/blood-2010-10-311761
Wojtaszek J, Lee CJ, D’Souza S, Minesinger B, Kim H, D’Andrea AD, Walker GC, Zhou P (2012) Structural basis of Rev1-mediated assembly of a quaternary vertebrate translesion polymerase complex consisting of Rev1, heterodimeric polymerase (Pol) zeta, and Pol kappa. J Biol Chem 287:33836–33846. https://doi.org/10.1074/jbc.M112.394841
Wu Y, Brosh RM Jr (2009) FANCJ helicase operates in the Fanconi Anemia DNA repair pathway and the response to replicational stress. Curr Mol Med 9:470–482. https://doi.org/10.2174/156652409788167159
Wu CG, Spies M (2016) G-quadruplex recognition and remodeling by the FANCJ helicase. Nucleic Acids Res 44:8742–8753. https://doi.org/10.1093/nar/gkw574
Wu Y, Shin-ya K, Brosh RM Jr (2008) FANCJ helicase defective in Fanconia anemia and breast cancer unwinds G-quadruplex DNA to defend genomic stability. Mol Cell Biol 28:4116–4128. https://doi.org/10.1128/mcb.02210-07
Wu RA, Semlow DR, Kamimae-Lanning AN, Kochenova OV, Chistol G, Hodskinson MR, Amunugama R, Sparks JL, Wang M, Deng L, Mimoso CA, Low E, Patel KJ, Walter JC (2019) TRAIP is a master regulator of DNA interstrand crosslink repair. Nature 567:267–272. https://doi.org/10.1038/s41586-019-1002-0
Wu S, Zhou J, Zhang K, Chen H, Luo M, Lu Y, Sun Y, Chen Y (2020) Molecular mechanisms of PALB2 function and its role in breast cancer management. Front Oncol 10:301. https://doi.org/10.3389/fonc.2020.00301
Xue Y, Li Y, Guo R, Ling C, Wang W (2008) FANCM of the Fanconi anemia core complex is required for both monoubiquitination and DNA repair. Hum Mol Genet 17:1641–1652. https://doi.org/10.1093/hmg/ddn054
Yagasaki H, Oda T, Adachi D, Nakajima T, Nakahata T, Asano S, Yamashita T (2003) Two common founder mutations of the fanconi anemia group G gene FANCG/XRCC9 in the Japanese population. Hum Mutat 21:555. https://doi.org/10.1002/humu.9142
Yamashita T, Wu N, Kupfer G, Corless C, Joenje H, Grompe M, D’Andrea AD (1996) Clinical variability of Fanconi anemia (type C) results from expression of an amino terminal truncated Fanconi anemia complementation group C polypeptide with partial activity. Blood 87:4424–4432
Yan Z, Delannoy M, Ling C, Daee D, Osman F, Muniandy PA, Shen X, Oostra AB, Du H, Steltenpool J, Lin T, Schuster B, Decaillet 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 (2010) A histone-fold complex and FANCM form a conserved DNA-remodeling complex to maintain genome stability. Mol Cell 37:865–878. https://doi.org/10.1016/j.molcel.2010.01.039
Yan Z, Guo R, Paramasivam M, Shen W, Ling C, Fox D 3rd, Wang Y, Oostra AB, Kuehl J, Lee DY, Takata M, Hoatlin ME, Schindler D, Joenje H, de Winter JP, Li L, Seidman MM, Wang W (2012) A ubiquitin-binding protein, FAAP20, links RNF8-mediated ubiquitination to the Fanconi anemia DNA repair network. Mol Cell 47:61–75. https://doi.org/10.1016/j.molcel.2012.05.026
Yang K, Moldovan GL, Vinciguerra P, Murai J, Takeda S, D’Andrea AD (2011) Regulation of the Fanconi anemia pathway by a SUMO-like delivery network. Genes Dev 25:1847–1858. https://doi.org/10.1101/gad.17020911
Yang Z, Wu XS, Wei Y, Polyanskaya SA, Iyer SV, Jung M, Lach FP, Adelman ER, Klingbeil O, Milazzo JP, Kramer M, Demerdash OE, Chang K, Goodwin S, Hodges E, McCombie WR, Figueroa ME, Smogorzewska A, Vakoc CR (2021) Transcriptional silencing of ALDH2 confers a dependency on Fanconi anemia proteins in acute myeloid leukemia. Cancer Discov 11:2300–2315. https://doi.org/10.1158/2159-8290.Cd-20-1542
Yuan F, Qian L, Zhao X, Liu JY, Song L, D’Urso G, Jain C, Zhang Y (2012) Fanconi anemia complementation group A (FANCA) protein has intrinsic affinity for nucleic acids with preference for single-stranded forms. J Biol Chem 287:4800–4807. https://doi.org/10.1074/jbc.M111.315366
Zhang J, Zhao D, Wang H, Lin CJ, Fei P (2008) FANCD2 monoubiquitination provides a link between the HHR6 and FA-BRCA pathways. Cell Cycle 7:407–413. https://doi.org/10.4161/cc.7.3.5156
Zhang F, Ma J, Wu J, Ye L, Cai H, Xia B, Yu X (2009) PALB2 links BRCA1 and BRCA2 in the DNA-damage response. Curr Biol 19:524–529. https://doi.org/10.1016/j.cub.2009.02.018
Zhang J, Dewar JM, Budzowska M, Motnenko A, Cohn MA, Walter JC (2015) DNA interstrand cross-link repair requires replication-fork convergence. Nat Struct Mol Biol 22:242–247. https://doi.org/10.1038/nsmb.2956
Zhi G, Wilson JB, Chen X, Krause DS, Xiao Y, Jones NJ, Kupfer GM (2009) Fanconi anemia complementation group FANCD2 protein serine 331 phosphorylation is important for fanconi anemia pathway function and BRCA2 interaction. Cancer Res 69:8775–8783. https://doi.org/10.1158/0008-5472.Can-09-2312
Acknowledgements
We thank Leah Dobossy and Kaitlin White for their critical reading of the manuscript. Members of the Noguchi laboratory are thanked for their support and encouragement.
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This work was supported by the National Institute of Health (F31-AA027133 to JDP) and the W. W. Smith Charitable Trust (#C1706 and #C2007 to EN).
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Peake, J.D., Noguchi, E. Fanconi anemia: current insights regarding epidemiology, cancer, and DNA repair. Hum Genet 141, 1811–1836 (2022). https://doi.org/10.1007/s00439-022-02462-9
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DOI: https://doi.org/10.1007/s00439-022-02462-9