The Fanconi Anaemia Pathway: New Players and New Functions

Overview

Journal Nat Rev Mol Cell Biol

Specialties Cell Biology
Molecular Biology

Date 2016 May 6

PMID 27145721

Citations 385

Authors

Raphael Ceccaldi

Prabha Sarangi

Alan D DAndrea

Affiliations

Soon will be listed here.

Abstract

The Fanconi anaemia pathway repairs DNA interstrand crosslinks (ICLs) in the genome. Our understanding of this complex pathway is still evolving, as new components continue to be identified and new biochemical systems are used to elucidate the molecular steps of repair. The Fanconi anaemia pathway uses components of other known DNA repair processes to achieve proper repair of ICLs. Moreover, Fanconi anaemia proteins have functions in genome maintenance beyond their canonical roles of repairing ICLs. Such functions include the stabilization of replication forks and the regulation of cytokinesis. Thus, Fanconi anaemia proteins are emerging as master regulators of genomic integrity that coordinate several repair processes. Here, we summarize our current understanding of the functions of the Fanconi anaemia pathway in ICL repair, together with an overview of its connections with other repair pathways and its emerging roles in genome maintenance.

Citing Articles

Inhibition of the STAT3/Fanconi anemia axis is synthetic lethal with PARP inhibition in breast cancer.

Rouault C, Bansard L, Martinez-Balsalobre E, Bonnet C, Wicinski J, Lin S Nat Commun. 2025; 16(1):2159.

PMID: 40038300 PMC: 11880418. DOI: 10.1038/s41467-025-57476-4.

The Development of ATM Inhibitors in Cancer Therapy.

Ampolini E, Jimenez-Sainz J, Long D Target Oncol. 2025; .

PMID: 40024979 DOI: 10.1007/s11523-025-01136-6.

Unveiling causal immune cell-gene associations in multiple myeloma: insights from systematic reviews and Mendelian randomization analyses.

Zhang H, Zhang L, Lian J, Kou Z, Zhu Y, Ma L Front Med (Lausanne). 2025; 12:1456732.

PMID: 39911859 PMC: 11794323. DOI: 10.3389/fmed.2025.1456732.

REV7: a small but mighty regulator of genome maintenance and cancer development.

Maggs L, McVey M Front Oncol. 2025; 14:1516165.

PMID: 39839778 PMC: 11747621. DOI: 10.3389/fonc.2024.1516165.

Inhibition of DEK restores hematopoietic stem cell function in Fanconi anemia.

Chen Z, Wu F, Li Y, Li L, Lei Y, Gao S J Exp Med. 2025; 222(3.

PMID: 39836085 PMC: 11748990. DOI: 10.1084/jem.20241248.

References

Klein Douwel D, Boonen R, Long D, Szypowska A, Raschle M, Walter J . XPF-ERCC1 acts in Unhooking DNA interstrand crosslinks in cooperation with FANCD2 and FANCP/SLX4. Mol Cell. 2014; 54(3):460-71. PMC: 5067070. DOI: 10.1016/j.molcel.2014.03.015. View

Wojtaszek J, Lee C, DSouza S, Minesinger B, Kim H, DAndrea A . Structural basis of Rev1-mediated assembly of a quaternary vertebrate translesion polymerase complex consisting of Rev1, heterodimeric polymerase (Pol) ζ, and Pol κ. J Biol Chem. 2012; 287(40):33836-46. PMC: 3460478. DOI: 10.1074/jbc.M112.394841. View

Kelland L . The resurgence of platinum-based cancer chemotherapy. Nat Rev Cancer. 2007; 7(8):573-84. DOI: 10.1038/nrc2167. View

Kim J, Parmar K, Huang M, Weinstock D, Ruit C, Kutok J . Inactivation of murine Usp1 results in genomic instability and a Fanconi anemia phenotype. Dev Cell. 2009; 16(2):314-20. PMC: 3134285. DOI: 10.1016/j.devcel.2009.01.001. View

Nijman S, Huang T, Dirac A, Brummelkamp T, Kerkhoven R, DAndrea A . The deubiquitinating enzyme USP1 regulates the Fanconi anemia pathway. Mol Cell. 2005; 17(3):331-9. DOI: 10.1016/j.molcel.2005.01.008. View

Smogorzewska A, Matsuoka S, Vinciguerra P, McDonald 3rd E, Hurov K, Luo J . Identification of the FANCI protein, a monoubiquitinated FANCD2 paralog required for DNA repair. Cell. 2007; 129(2):289-301. PMC: 2175179. DOI: 10.1016/j.cell.2007.03.009. View

Yan Z, Delannoy M, Ling C, Daee D, Osman F, Muniandy P . A histone-fold complex and FANCM form a conserved DNA-remodeling complex to maintain genome stability. Mol Cell. 2010; 37(6):865-78. PMC: 2847587. DOI: 10.1016/j.molcel.2010.01.039. View

Zhou W, Otto E, Cluckey A, Airik R, Hurd T, Chaki M . FAN1 mutations cause karyomegalic interstitial nephritis, linking chronic kidney failure to defective DNA damage repair. Nat Genet. 2012; 44(8):910-5. PMC: 3412140. DOI: 10.1038/ng.2347. View

Liang C, Zhan B, Yoshikawa Y, Haas W, Gygi S, Cohn M . UHRF1 is a sensor for DNA interstrand crosslinks and recruits FANCD2 to initiate the Fanconi anemia pathway. Cell Rep. 2015; 10(12):1947-56. PMC: 4386029. DOI: 10.1016/j.celrep.2015.02.053. View

10.

Segui N, Mina L, Lazaro C, Sanz-Pamplona R, Pons T, Navarro M . Germline Mutations in FAN1 Cause Hereditary Colorectal Cancer by Impairing DNA Repair. Gastroenterology. 2015; 149(3):563-6. DOI: 10.1053/j.gastro.2015.05.056. View

11.

Geng L, Huntoon C, Karnitz L . RAD18-mediated ubiquitination of PCNA activates the Fanconi anemia DNA repair network. J Cell Biol. 2010; 191(2):249-57. PMC: 2958487. DOI: 10.1083/jcb.201005101. View

12.

Ameziane N, May P, Haitjema A, van de Vrugt H, van Rossum-Fikkert S, Ristic D . A novel Fanconi anaemia subtype associated with a dominant-negative mutation in RAD51. Nat Commun. 2015; 6:8829. PMC: 4703882. DOI: 10.1038/ncomms9829. View

13.

Howard S, Yanez D, Stark J . DNA damage response factors from diverse pathways, including DNA crosslink repair, mediate alternative end joining. PLoS Genet. 2015; 11(1):e1004943. PMC: 4309583. DOI: 10.1371/journal.pgen.1004943. View

14.

Kim H, Yang K, Dejsuphong D, DAndrea A . Regulation of Rev1 by the Fanconi anemia core complex. Nat Struct Mol Biol. 2012; 19(2):164-70. PMC: 3280818. DOI: 10.1038/nsmb.2222. View

15.

Shimamura A, Alter B . Pathophysiology and management of inherited bone marrow failure syndromes. Blood Rev. 2010; 24(3):101-22. PMC: 3733544. DOI: 10.1016/j.blre.2010.03.002. View

16.

Williams S, Longerich S, Sung P, Vaziri C, Kupfer G . The E3 ubiquitin ligase RAD18 regulates ubiquitylation and chromatin loading of FANCD2 and FANCI. Blood. 2011; 117(19):5078-87. PMC: 3109534. DOI: 10.1182/blood-2010-10-311761. View

17.

Huang J, Liu S, Bellani M, Thazhathveetil A, Ling C, de Winter J . The DNA translocase FANCM/MHF promotes replication traverse of DNA interstrand crosslinks. Mol Cell. 2013; 52(3):434-46. PMC: 3880019. DOI: 10.1016/j.molcel.2013.09.021. View

18.

Luebben S, Kawabata T, Johnson C, OSullivan M, Shima N . A concomitant loss of dormant origins and FANCC exacerbates genome instability by impairing DNA replication fork progression. Nucleic Acids Res. 2014; 42(9):5605-15. PMC: 4027174. DOI: 10.1093/nar/gku170. View

19.

Kannouche P, Wing J, Lehmann A . Interaction of human DNA polymerase eta with monoubiquitinated PCNA: a possible mechanism for the polymerase switch in response to DNA damage. Mol Cell. 2004; 14(4):491-500. DOI: 10.1016/s1097-2765(04)00259-x. View

20.

Hodskinson M, Silhan J, Crossan G, Garaycoechea J, Mukherjee S, Johnson C . Mouse SLX4 is a tumor suppressor that stimulates the activity of the nuclease XPF-ERCC1 in DNA crosslink repair. Mol Cell. 2014; 54(3):472-84. PMC: 4017094. DOI: 10.1016/j.molcel.2014.03.014. View