Deciphering the role of post-translational modifications in fanconi anemia proteins and their influence on tumorigenesis.

Journal

Cancer gene therapy

ISSN: 1476-5500

Titre abrégé: Cancer Gene Ther

Pays: England

ID NLM: 9432230

Informations de publication

Date de publication:
15 Jun 2024

Historique:

received: 03 04 2024

accepted: 04 06 2024

revised: 01 06 2024

medline: 16 6 2024

pubmed: 16 6 2024

entrez: 15 6 2024

Statut: aheadofprint

Résumé

Fanconi anemia (FA) is an autosomal or X-linked human disease, characterized by bone marrow failure, cancer susceptibility and various developmental abnormalities. So far, at least 22 FA genes (FANCA-W) have been identified. Germline inactivation of any one of these FA genes causes FA symptoms. Proteins encoded by FA genes are involved in the Fanconi anemia pathway, which is known for its roles in DNA inter-strand crosslinks (ICLs) repair. Besides, its roles in genome maintenance upon replication stress has also been reported. Post-translational modifications (PTMs) of FA proteins, particularly phosphorylation and ubiquitination, emerge as critical determinants in the activation of the FA pathway during ICL repair or replication stress response. Consequent inactivation of the FA pathway engenders heightened chromosomal instability, thereby constituting a genetic susceptibility conducive to cancer predisposition and the exacerbation of tumorigenesis. In this review, we have combined recent structural analysis of FA proteins and summarized knowledge on the functions of different PTMs in regulating FA pathways, and discuss potential contributions stemming from mutations at PTMs to the genesis and progression of tumorigenesis.

Identifiants

DOI: 10.1038/s41417-024-00797-1 PMID: 38879655

pubmed: 38879655

doi: 10.1038/s41417-024-00797-1

pii: 10.1038/s41417-024-00797-1

doi:

Types de publication

Journal Article Review

Langues

eng

Sous-ensembles de citation

Subventions

Organisme : Natural Science Foundation of Hubei Province (Hubei Provincial Natural Science Foundation)

ID : 2024AFB473

Informations de copyright

Références

Dokal I, Vulliamy T. Inherited bone marrow failure syndromes. Haematologica. 2010;95:1236–40.

pubmed: 20675743 pmcid: 2913069 doi: 10.3324/haematol.2010.025619

Rosenberg PS, Tamary H, Alter BP. 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. 2011;155a:1877–83.

pubmed: 21739583 doi: 10.1002/ajmg.a.34087

Gluckman E, Auerbach AD, Horowitz MM, Sobocinski KA, Ash RC, Bortin MM, et al. Bone marrow transplantation for Fanconi anemia. Blood. 1995;86:2856–62.

pubmed: 7670120 doi: 10.1182/blood.V86.7.2856.2856

D’Andrea AD. Susceptibility pathways in Fanconi’s anemia and breast cancer. N Engl J Med. 2010;362:1909–19.

pubmed: 20484397 pmcid: 3069698 doi: 10.1056/NEJMra0809889

Green AM, Kupfer GM. Fanconi anemia. Hematol Oncol Clin North Am. 2009;23:193–214.

pubmed: 19327579 pmcid: 5912671 doi: 10.1016/j.hoc.2009.01.008

Kutler DI, Auerbach AD, Satagopan J, Giampietro PF, Batish SD, Huvos AG, et al. High incidence of head and neck squamous cell carcinoma in patients with Fanconi anemia. Arch Otolaryngol Head Neck Surg. 2003;129:106–12.

pubmed: 12525204 doi: 10.1001/archotol.129.1.106

Kutler DI, Patel KR, Auerbach AD, Kennedy J, Lach FP, Sanborn E, et al. Natural history and management of Fanconi anemia patients with head and neck cancer: A 10-year follow-up. Laryngoscope. 2016;126:870–9.

pubmed: 26484938 doi: 10.1002/lary.25726

Kutler DI, Singh B, Satagopan J, Batish SD, Berwick M, Giampietro PF, et al. A 20-year perspective on the International Fanconi Anemia Registry (IFAR). Blood. 2003;101:1249–56.

pubmed: 12393516 doi: 10.1182/blood-2002-07-2170

Nepal M, Che R, Zhang J, Ma C, Fei P. Fanconi anemia signaling and cancer. Trends cancer. 2017;3:840–56.

pubmed: 29198440 pmcid: 5819365 doi: 10.1016/j.trecan.2017.10.005

Chaudhury I, Sareen A, Raghunandan M, Sobeck A. FANCD2 regulates BLM complex functions independently of FANCI to promote replication fork recovery. Nucleic acids Res. 2013;41:6444–59.

pubmed: 23658231 pmcid: 3711430 doi: 10.1093/nar/gkt348

Naim V, Rosselli F. The FANC pathway and BLM collaborate during mitosis to prevent micro-nucleation and chromosome abnormalities. Nat Cell Biol. 2009;11:761–8.

pubmed: 19465921 doi: 10.1038/ncb1883

Okamoto Y, Iwasaki WM, Kugou K, Takahashi KK, Oda A, Sato K, et al. Replication stress induces accumulation of FANCD2 at central region of large fragile genes. Nucleic acids Res. 2018;46:2932–44.

pubmed: 29394375 pmcid: 5888676 doi: 10.1093/nar/gky058

García-Rubio ML, Pérez-Calero C, Barroso SI, Tumini E, Herrera-Moyano E, Rosado IV, et al. The Fanconi anemia pathway protects genome integrity from R-loops. PLoS Genet. 2015;11:e1005674.

pubmed: 26584049 pmcid: 4652862 doi: 10.1371/journal.pgen.1005674

Schwab RA, Nieminuszczy J, Shah F, Langton J, Lopez Martinez D, Liang CC, et al. The Fanconi anemia pathway maintains genome stability by coordinating replication and transcription. Mol Cell. 2015;60:351–61.

pubmed: 26593718 pmcid: 4644232 doi: 10.1016/j.molcel.2015.09.012

Xu X, Xu Y, Guo R, Xu R, Fu C, Xing M, et al. Fanconi anemia proteins participate in a break-induced-replication-like pathway to counter replication stress. Nat Struct Mol Biol. 2021;28:487–500.

pubmed: 34117478 doi: 10.1038/s41594-021-00602-9

Ceccaldi R, Sarangi P, D’Andrea AD. The Fanconi anaemia pathway: new players and new functions. Nat Rev Mol Cell Biol. 2016;17:337–49.

pubmed: 27145721 doi: 10.1038/nrm.2016.48

Ishiai M, Kitao H, Smogorzewska A, Tomida J, Kinomura A, Uchida E, et al. FANCI phosphorylation functions as a molecular switch to turn on the Fanconi anemia pathway. Nat Struct Mol Biol. 2008;15:1138–46.

pubmed: 18931676 pmcid: 3293454 doi: 10.1038/nsmb.1504

Wang R, Wang S, Dhar A, Peralta C, Pavletich NP. DNA clamp function of the monoubiquitinated Fanconi anaemia ID complex. Nature. 2020;580:278–82.

pubmed: 32269332 pmcid: 7398534 doi: 10.1038/s41586-020-2110-6

Tan W, van Twest S, Leis A, Bythell-Douglas R, Murphy VJ, Sharp M, et al. Monoubiquitination by the human Fanconi anemia core complex clamps FANCI:FANCD2 on DNA in filamentous arrays. eLife. 2020;9:e54128.

pubmed: 32167469 pmcid: 7156235 doi: 10.7554/eLife.54128

Alcon P, Shakeel S, Chen ZA, Rappsilber J, Patel KJ, Passmore LA. FANCD2-FANCI is a clamp stabilized on DNA by monoubiquitination of FANCD2 during DNA repair. Nat Struct Mol Biol. 2020;27:240–8.

pubmed: 32066963 pmcid: 7067600 doi: 10.1038/s41594-020-0380-1

Wang S, Wang R, & Peralta, Peralta C, Yaseen A, Pavletich NP. Structure of the Fanconi Anemia Core-UBE2T complex poised to ubiquitinate bound FANCI-FANCD2. bioRxiv. 2019;854158.

Rennie ML, Arkinson C, Chaugule VK, Toth R, Walden H. Structural basis of FANCD2 deubiquitination by USP1-UAF1. Nat Struct Mol Biol. 2021;28:356–64.

pubmed: 33795880 doi: 10.1038/s41594-021-00576-8

Wang S, Wang R, Peralta C, Yaseen A, Pavletich NP. Structure of the FA core ubiquitin ligase closing the ID clamp on DNA. Nat Struct Mol Biol. 2021;28:300–9.

pubmed: 33686268 pmcid: 8378520 doi: 10.1038/s41594-021-00568-8

Sijacki T, Alcón P, Chen ZA, McLaughlin SH, Shakeel S, Rappsilber J, et al. The DNA-damage kinase ATR activates the FANCD2-FANCI clamp by priming it for ubiquitination. Nat Struct Mol Biol. 2022;29:881–90.

pubmed: 36050501 pmcid: 7613635 doi: 10.1038/s41594-022-00820-9

Cardozo T, Pagano M. The SCF ubiquitin ligase: insights into a molecular machine. Nat Rev Mol Cell Biol. 2004;5:739–51.

pubmed: 15340381 doi: 10.1038/nrm1471

Ohta T, Fukuda M. Ubiquitin and breast cancer. Oncogene. 2004;23:2079–88.

pubmed: 15021895 doi: 10.1038/sj.onc.1207371

Hershko A, Heller H, Elias S, Ciechanover A. Components of ubiquitin-protein ligase system. Resolution, affinity purification, and role in protein breakdown. J Biol Chem. 1983;258:8206–14.

pubmed: 6305978 doi: 10.1016/S0021-9258(20)82050-X

Ciechanover A, Elias S, Heller H, Hershko A. “Covalent affinity” purification of ubiquitin-activating enzyme. J Biol Chem. 1982;257:2537–42.

pubmed: 6277904 doi: 10.1016/S0021-9258(18)34957-3

Nijman SM, Luna-Vargas MP, Velds A, Brummelkamp TR, Dirac AM, Sixma TK, et al. A genomic and functional inventory of deubiquitinating enzymes. Cell. 2005;123:773–86.

pubmed: 16325574 doi: 10.1016/j.cell.2005.11.007

Sowa ME, Bennett EJ, Gygi SP, Harper JW. Defining the human deubiquitinating enzyme interaction landscape. Cell. 2009;138:389–403.

pubmed: 19615732 pmcid: 2716422 doi: 10.1016/j.cell.2009.04.042

Xue Y, Li Y, Guo R, Ling C, Wang W. FANCM of the Fanconi anemia core complex is required for both monoubiquitination and DNA repair. Hum Mol Genet. 2008;17:1641–52.

pubmed: 18285517 pmcid: 2902294 doi: 10.1093/hmg/ddn054

Collis SJ, Ciccia A, Deans AJ, Horejsí Z, Martin JS, Maslen SL, et al. FANCM and FAAP24 function in ATR-mediated checkpoint signaling independently of the Fanconi anemia core complex. Mol cell. 2008;32:313–24.

pubmed: 18995830 doi: 10.1016/j.molcel.2008.10.014

Walden H, Deans AJ. The Fanconi anemia DNA repair pathway: structural and functional insights into a complex disorder. Annu Rev Biophys. 2014;43:257–78.

pubmed: 24773018 doi: 10.1146/annurev-biophys-051013-022737

Cole AR, Lewis LP, Walden H. The structure of the catalytic subunit FANCL of the Fanconi anemia core complex. Nat Struct Mol Biol. 2010;17:294–8.

pubmed: 20154706 pmcid: 2929457 doi: 10.1038/nsmb.1759

Shakeel S, Rajendra E, Alcón P, O’Reilly F, Chorev DS, Maslen S, et al. Structure of the Fanconi anaemia monoubiquitin ligase complex. Nature. 2019;575:234–7.

pubmed: 31666700 pmcid: 6858856 doi: 10.1038/s41586-019-1703-4

Jeong E, Lee SG, Kim HS, Yang J, Shin J, Kim Y, et al. Structural basis of the fanconi anemia-associated mutations within the FANCA and FANCG complex. Nucleic acids Res. 2020;48:3328–42.

pubmed: 32002546 pmcid: 7102982 doi: 10.1093/nar/gkaa062

Li L, Tan W, Deans AJ. Structural insight into FANCI-FANCD2 monoubiquitination. Essays Biochem. 2020;64:807–17.

pubmed: 32725171 pmcid: 7588663 doi: 10.1042/EBC20200001

Rajendra E, Oestergaard VH, Langevin F, Wang M, Dornan GL, Patel KJ, et al. The genetic and biochemical basis of FANCD2 monoubiquitination. Mol cell. 2014;54:858–69.

pubmed: 24905007 pmcid: 4051986 doi: 10.1016/j.molcel.2014.05.001

Wang AT, Smogorzewska A. SnapShot: Fanconi anemia and associated proteins. Cell. 2015;160:354.-.e1.

doi: 10.1016/j.cell.2014.12.031

Blom E, van de Vrugt HJ, de Vries Y, de Winter JP, Arwert F, Joenje H. Multiple TPR motifs characterize the Fanconi anemia FANCG protein. DNA Repair (Amst). 2004;3:77–84.

pubmed: 14697762 doi: 10.1016/j.dnarep.2003.09.007

Leung JW, Wang Y, Fong KW, Huen MS, Li L, Chen J. Fanconi anemia (FA) binding protein FAAP20 stabilizes FA complementation group A (FANCA) and participates in interstrand cross-link repair. Proc Natl Acad Sci USA. 2012;109:4491–6.

pubmed: 22396592 pmcid: 3311328 doi: 10.1073/pnas.1118720109

Hira A, Yoshida K, Sato K, Okuno Y, Shiraishi Y, Chiba K, et al. Mutations in the gene encoding the E2 conjugating enzyme UBE2T cause Fanconi anemia. Am J Hum Genet. 2015;96:1001–7.

pubmed: 26046368 pmcid: 4457949 doi: 10.1016/j.ajhg.2015.04.022

Miles JA, Frost MG, Carroll E, Rowe ML, Howard MJ, Sidhu A, et al. The Fanconi Anemia DNA Repair Pathway Is Regulated by an Interaction between Ubiquitin and the E2-like Fold Domain of FANCL. J Biol Chem. 2015;290:20995–1006.

pubmed: 26149689 pmcid: 4543658 doi: 10.1074/jbc.M115.675835

Rickman KA, Lach FP, Abhyankar A, Donovan FX, Sanborn EM, Kennedy JA, et al. Deficiency of UBE2T, the E2 ubiquitin ligase necessary for FANCD2 and FANCI ubiquitination, causes FA-T subtype of fanconi anemia. Cell Rep. 2015;12:35–41.

pubmed: 26119737 pmcid: 4497947 doi: 10.1016/j.celrep.2015.06.014

Alpi AF, Pace PE, Babu MM, Patel KJ. Mechanistic insight into site-restricted monoubiquitination of FANCD2 by Ube2t, FANCL, and FANCI. Mol cell. 2008;32:767–77.

pubmed: 19111657 doi: 10.1016/j.molcel.2008.12.003

Liang CC, Li Z, Lopez-Martinez D, Nicholson WV, Vénien-Bryan C, Cohn MA. The FANCD2-FANCI complex is recruited to DNA interstrand crosslinks before monoubiquitination of FANCD2. Nat Commun. 2016;7:12124.

pubmed: 27405460 pmcid: 4947157 doi: 10.1038/ncomms12124

Swuec P, Renault L, Borg A, Shah F, Murphy VJ, van Twest S, et al. The FA core complex contains a homo-dimeric catalytic module for the symmetric mono-ubiquitination of FANCI-FANCD2. Cell Rep. 2017;18:611–23.

pubmed: 27986592 doi: 10.1016/j.celrep.2016.11.013

Sims AE, Spiteri E, Sims RJ 3rd, Arita AG, Lach FP, Landers T, et al. FANCI is a second monoubiquitinated member of the Fanconi anemia pathway. Nat Struct Mol Biol. 2007;14:564–7.

pubmed: 17460694 doi: 10.1038/nsmb1252

Smogorzewska A, Matsuoka S, Vinciguerra P, McDonald ER 3rd, Hurov KE, Luo J, et al. Identification of the FANCI protein, a monoubiquitinated FANCD2 paralog required for DNA repair. Cell 2007;129:289–301.

pubmed: 17412408 pmcid: 2175179 doi: 10.1016/j.cell.2007.03.009

Geng L, Huntoon CJ, Karnitz LM. RAD18-mediated ubiquitination of PCNA activates the Fanconi anemia DNA repair network. J Cell Biol. 2010;191:249–57.

pubmed: 20937699 pmcid: 2958487 doi: 10.1083/jcb.201005101

Williams SA, Longerich S, Sung P, Vaziri C, Kupfer GM. The E3 ubiquitin ligase RAD18 regulates ubiquitylation and chromatin loading of FANCD2 and FANCI. Blood. 2011;117:5078–87.

pubmed: 21355096 pmcid: 3109534 doi: 10.1182/blood-2010-10-311761

Song IY, Palle K, Gurkar A, Tateishi S, Kupfer GM, Vaziri C. Rad18-mediated translesion synthesis of bulky DNA adducts is coupled to activation of the Fanconi anemia DNA repair pathway. J Biol Chem. 2010;285:31525–36.

pubmed: 20675655 pmcid: 2951227 doi: 10.1074/jbc.M110.138206

Howlett NG, Harney JA, Rego MA, Kolling FWt, Glover TW. Functional interaction between the Fanconi Anemia D2 protein and proliferating cell nuclear antigen (PCNA) via a conserved putative PCNA interaction motif. J Biol Chem. 2009;284:28935–42.

pubmed: 19704162 pmcid: 2781439 doi: 10.1074/jbc.M109.016352

Guervilly JH, Macé-Aimé G, Rosselli F. Loss of CHK1 function impedes DNA damage-induced FANCD2 monoubiquitination but normalizes the abnormal G2 arrest in Fanconi anemia. Hum Mol Genet. 2008;17:679–89.

pubmed: 18029388 doi: 10.1093/hmg/ddm340

Arkinson C, Chaugule VK, Toth R, Walden H. Specificity for deubiquitination of monoubiquitinated FANCD2 is driven by the N-terminus of USP1. Life Sci alliance. 2018;1:e201800162.

pubmed: 30456385 pmcid: 6238601 doi: 10.26508/lsa.201800162

Cohn MA, Kowal P, Yang K, Haas W, Huang TT, Gygi SP, et al. A UAF1-containing multisubunit protein complex regulates the Fanconi anemia pathway. Mol cell. 2007;28:786–97.

pubmed: 18082604 doi: 10.1016/j.molcel.2007.09.031

Dharadhar S, van Dijk WJ, Scheffers S, Fish A, Sixma TK. Insert L1 is a central hub for allosteric regulation of USP1 activity. EMBO Rep. 2021;22:e51749.

pubmed: 33619839 pmcid: 8024992 doi: 10.15252/embr.202051749

Oestergaard VH, Langevin F, Kuiken HJ, Pace P, Niedzwiedz W, Simpson LJ, et al. Deubiquitination of FANCD2 is required for DNA crosslink repair. Mol cell. 2007;28:798–809.

pubmed: 18082605 pmcid: 2148256 doi: 10.1016/j.molcel.2007.09.020

Kim JM, Parmar K, Huang M, Weinstock DM, Ruit CA, Kutok JL, et al. Inactivation of murine Usp1 results in genomic instability and a Fanconi anemia phenotype. Developmental Cell. 2009;16:314–20.

pubmed: 19217432 pmcid: 3134285 doi: 10.1016/j.devcel.2009.01.001

Montes de Oca R, Andreassen PR, Margossian SP, Gregory RC, Taniguchi T, Wang X, et al. Regulated interaction of the Fanconi anemia protein, FANCD2, with chromatin. Blood. 2005;105:1003–9.

pubmed: 15454491 doi: 10.1182/blood-2003-11-3997

Yamamoto KN, Kobayashi S, Tsuda M, Kurumizaka H, Takata M, Kono K, et al. Involvement of SLX4 in interstrand cross-link repair is regulated by the Fanconi anemia pathway. Proc Natl Acad Sci USA. 2011;108:6492–6.

pubmed: 21464321 pmcid: 3080998 doi: 10.1073/pnas.1018487108

Joo W, Xu G, Persky NS, Smogorzewska A, Rudge DG, Buzovetsky O, et al. Structure of the FANCI-FANCD2 complex: insights into the Fanconi anemia DNA repair pathway. Sci (N. Y, NY). 2011;333:312–6.

doi: 10.1126/science.1205805

Rennie ML, Lemonidis K, Arkinson C, Chaugule VK, Clarke M, Streetley J, et al. Differential functions of FANCI and FANCD2 ubiquitination stabilize ID2 complex on DNA. EMBO Rep. 2020;21:e50133.

pubmed: 32510829 pmcid: 7332966 doi: 10.15252/embr.202050133

Roach PJ. Multisite and hierarchal protein phosphorylation. J Biol Chem. 1991;266:14139–42.

pubmed: 1650349 doi: 10.1016/S0021-9258(18)98653-9

Cohen P. The regulation of protein function by multisite phosphorylation-a 25 year update. Trends biochemical Sci. 2000;25:596–601.

doi: 10.1016/S0968-0004(00)01712-6

Holmberg CI, Tran SE, Eriksson JE, Sistonen L. Multisite phosphorylation provides sophisticated regulation of transcription factors. Trends biochemical Sci. 2002;27:619–27.

doi: 10.1016/S0968-0004(02)02207-7

Shi Y. Serine/threonine phosphatases: mechanism through structure. Cell. 2009;139:468–84.

pubmed: 19879837 doi: 10.1016/j.cell.2009.10.006

Maréchal A, Zou L. DNA damage sensing by the ATM and ATR kinases. Cold Spring Harb Perspect Biol. 2013;5:a012716.

pubmed: 24003211 pmcid: 3753707 doi: 10.1101/cshperspect.a012716

Ma M, Rodriguez A, Sugimoto K. Activation of ATR-related protein kinase upon DNA damage recognition. Curr Genet. 2020;66:327–33.

pubmed: 31624858 doi: 10.1007/s00294-019-01039-w

Smith J, Tho LM, Xu N, Gillespie DA. The ATM-Chk2 and ATR-Chk1 pathways in DNA damage signaling and cancer. Adv Cancer Res. 2010;108:73–112.

pubmed: 21034966 doi: 10.1016/B978-0-12-380888-2.00003-0

Traven A, Heierhorst J. SQ/TQ cluster domains: concentrated ATM/ATR kinase phosphorylation site regions in DNA-damage-response proteins. Bioessays. 2005;27:397–407.

pubmed: 15770685 doi: 10.1002/bies.20204

Smits VA, Warmerdam DO, Martin Y, Freire R. Mechanisms of ATR-mediated checkpoint signalling. Front Biosci (Landmark Ed). 2010;15:840–53.

pubmed: 20515729 doi: 10.2741/3649

Nam EA, Cortez D. ATR signalling: more than meeting at the fork. Biochem J. 2011;436:527–36.

pubmed: 21615334 doi: 10.1042/BJ20102162

Cimprich KA, Cortez D. ATR: an essential regulator of genome integrity. Nat Rev Mol cell Biol. 2008;9:616–27.

pubmed: 18594563 pmcid: 2663384 doi: 10.1038/nrm2450

Andreassen PR, D’Andrea AD, Taniguchi T. ATR couples FANCD2 monoubiquitination to the DNA-damage response. Genes Dev. 2004;18:1958–63.

pubmed: 15314022 pmcid: 514175 doi: 10.1101/gad.1196104

Cheung RS, Castella M, Abeyta A, Gafken PR, Tucker N, Taniguchi T. Ubiquitination-linked phosphorylation of the FANCI S/TQ cluster contributes to activation of the fanconi anemia I/D2 Complex. Cell Rep. 2017;19:2432–40.

pubmed: 28636932 pmcid: 5538132 doi: 10.1016/j.celrep.2017.05.081

Shigechi T, Tomida J, Sato K, Kobayashi M, Eykelenboom JK, Pessina F, et al. ATR-ATRIP kinase complex triggers activation of the Fanconi anemia DNA repair pathway. Cancer Res. 2012;72:1149–56.

pubmed: 22258451 doi: 10.1158/0008-5472.CAN-11-2904

Tan W, van Twest S, Murphy VJ, Deans AJ. ATR-mediated FANCI phosphorylation regulates both ubiquitination and deubiquitination of FANCD2. Front Cell Dev Biol. 2020;8:2.

pubmed: 32117957 pmcid: 7010609 doi: 10.3389/fcell.2020.00002

Tomida J, Itaya A, Shigechi T, Unno J, Uchida E, Ikura M, et al. A novel interplay between the Fanconi anemia core complex and ATR-ATRIP kinase during DNA cross-link repair. Nucleic acids Res. 2013;41:6930–41.

pubmed: 23723247 pmcid: 3737553 doi: 10.1093/nar/gkt467

Matsuoka S, Ballif BA, Smogorzewska A, McDonald ER 3rd, Hurov KE, Luo J, et al. ATM and ATR substrate analysis reveals extensive protein networks responsive to DNA damage. Sci (N. Y, NY). 2007;316:1160–6.

doi: 10.1126/science.1140321

Lanz MC, Dibitetto D, Smolka MB. DNA damage kinase signaling: checkpoint and repair at 30 years. EMBO J. 2019;38:e101801.

pubmed: 31393028 pmcid: 6745504 doi: 10.15252/embj.2019101801

Navadgi-Patil VM, Burgers PM. A tale of two tails: activation of DNA damage checkpoint kinase Mec1/ATR by the 9-1-1 clamp and by Dpb11/TopBP1. DNA Repair (Amst). 2009;8:996–1003.

pubmed: 19464966 doi: 10.1016/j.dnarep.2009.03.011

Zhi G, Wilson JB, Chen X, Krause DS, Xiao Y, Jones NJ, et al. Fanconi anemia complementation group FANCD2 protein serine 331 phosphorylation is important for fanconi anemia pathway function and BRCA2 interaction. Cancer Res. 2009;69:8775–83.

pubmed: 19861535 pmcid: 5912675 doi: 10.1158/0008-5472.CAN-09-2312

Cantres-Velez JA, Blaize JL, Vierra DA, Boisvert RA, Garzon JL, Piraino B, et al. Cyclin-dependent kinase-mediated phosphorylation of FANCD2 promotes mitotic fidelity. Mol Cell Biol. 2021;41:e0023421.

pubmed: 34096775 doi: 10.1128/MCB.00234-21

Ho GP, Margossian S, Taniguchi T, D’Andrea AD. Phosphorylation of FANCD2 on two novel sites is required for mitomycin C resistance. Mol Cell Biol. 2006;26:7005–15.

pubmed: 16943440 pmcid: 1592857 doi: 10.1128/MCB.02018-05

Taniguchi T, Garcia-Higuera I, Xu B, Andreassen PR, Gregory RC, Kim ST, et al. Convergence of the fanconi anemia and ataxia telangiectasia signaling pathways. Cell. 2002;109:459–72.

pubmed: 12086603 doi: 10.1016/S0092-8674(02)00747-X

Lopez-Martinez D, Kupculak M, Yang D, Yoshikawa Y, Liang CC, Wu R, et al. Phosphorylation of FANCD2 inhibits the FANCD2/FANCI complex and suppresses the fanconi anemia pathway in the absence of DNA damage. Cell Rep. 2019;27:2990–3005.e5.

pubmed: 31167143 pmcid: 6581795 doi: 10.1016/j.celrep.2019.05.003

Meetei AR, Medhurst AL, Ling C, Xue Y, Singh TR, Bier P, et al. A human ortholog of archaeal DNA repair protein Hef is defective in Fanconi anemia complementation group M. Nat Genet. 2005;37:958–63.

pubmed: 16116422 pmcid: 2704909 doi: 10.1038/ng1626

Singh TR, Ali AM, Paramasivam M, Pradhan A, Wahengbam K, Seidman MM, et al. ATR-dependent phosphorylation of FANCM at serine 1045 is essential for FANCM functions. Cancer Res. 2013;73:4300–10.

pubmed: 23698467 pmcid: 3732194 doi: 10.1158/0008-5472.CAN-12-3976

Kim JM, Kee Y, Gurtan A, D’Andrea AD. Cell cycle-dependent chromatin loading of the Fanconi anemia core complex by FANCM/FAAP24. Blood. 2008;111:5215–22.

pubmed: 18174376 pmcid: 2384144 doi: 10.1182/blood-2007-09-113092

Collins NB, Wilson JB, Bush T, Thomashevski A, Roberts KJ, Jones NJ, et al. ATR-dependent phosphorylation of FANCA on serine 1449 after DNA damage is important for FA pathway function. Blood. 2009;113:2181–90.

pubmed: 19109555 pmcid: 2652366 doi: 10.1182/blood-2008-05-154294

Wang X, Kennedy RD, Ray K, Stuckert P, Ellenberger T, D’Andrea AD. Chk1-mediated phosphorylation of FANCE is required for the Fanconi anemia/BRCA pathway. Mol Cell Biol. 2007;27:3098–108.

pubmed: 17296736 pmcid: 1899922 doi: 10.1128/MCB.02357-06

Qiao F, Mi J, Wilson JB, Zhi G, Bucheimer NR, Jones NJ, et al. Phosphorylation of fanconi anemia (FA) complementation group G protein, FANCG, at serine 7 is important for function of the FA pathway. J Biol Chem. 2004;279:46035–45.

pubmed: 15299017 doi: 10.1074/jbc.M408323200

Dao KH, Rotelli MD, Brown BR, Yates JE, Rantala J, Tognon C, et al. The PI3K/Akt1 pathway enhances steady-state levels of FANCL. Mol Biol Cell. 2013;24:2582–92.

pubmed: 23783032 pmcid: 3744951 doi: 10.1091/mbc.e13-03-0144

Woods NT, Mesquita RD, Sweet M, Carvalho MA, Li X, Liu Y, et al. Charting the landscape of tandem BRCT domain-mediated protein interactions. Sci Signal. 2012;5:rs6.

pubmed: 22990118 pmcid: 4064718 doi: 10.1126/scisignal.2002255

Hu WF, Krieger KL, Lagundžin D, Li X, Cheung RS, Taniguchi T, et al. CTDP1 regulates breast cancer survival and DNA repair through BRCT-specific interactions with FANCI. Cell Death Discov. 2019;5:105.

pubmed: 31240132 pmcid: 6584691 doi: 10.1038/s41420-019-0185-3

Vuono EA, Mukherjee A, Vierra DA, Adroved MM, Hodson C, Deans AJ, et al. The PTEN phosphatase functions cooperatively with the Fanconi anemia proteins in DNA crosslink repair. Sci Rep. 2016;6:36439.

pubmed: 27819275 pmcid: 5098254 doi: 10.1038/srep36439

Sato K, Toda K, Ishiai M, Takata M, Kurumizaka H. DNA robustly stimulates FANCD2 monoubiquitylation in the complex with FANCI. Nucleic acids Res. 2012;40:4553–61.

pubmed: 22287633 pmcid: 3378891 doi: 10.1093/nar/gks053

Bergink S, Jentsch S. Principles of ubiquitin and SUMO modifications in DNA repair. Nature. 2009;458:461–7.

pubmed: 19325626 doi: 10.1038/nature07963

Morris JR. SUMO in the mammalian response to DNA damage. Biochem Soc Trans. 2010;38:92–7.

pubmed: 20074042 doi: 10.1042/BST0380092

Bekker-Jensen S, Mailand N. The ubiquitin- and SUMO-dependent signaling response to DNA double-strand breaks. FEBS Lett. 2011;585:2914–9.

pubmed: 21664912 doi: 10.1016/j.febslet.2011.05.056

Xie J, Kim H, Moreau LA, Puhalla S, Garber J, Al Abo M, et al. RNF4-mediated polyubiquitination regulates the Fanconi anemia/BRCA pathway. J Clin Invest. 2015;125:1523–32.

pubmed: 25751062 pmcid: 4396491 doi: 10.1172/JCI79325

Gibbs-Seymour I, Oka Y, Rajendra E, Weinert BT, Passmore LA, Patel KJ, et al. Ubiquitin-SUMO circuitry controls activated fanconi anemia ID complex dosage in response to DNA damage. Mol Cell. 2015;57:150–64.

pubmed: 25557546 pmcid: 4416315 doi: 10.1016/j.molcel.2014.12.001

Guervilly JH, Takedachi A, Naim V, Scaglione S, Chawhan C, Lovera Y, et al. The SLX4 complex is a SUMO E3 ligase that impacts on replication stress outcome and genome stability. Mol cell. 2015;57:123–37.

pubmed: 25533188 doi: 10.1016/j.molcel.2014.11.014

Ouyang J, Garner E, Hallet A, Nguyen HD, Rickman KA, Gill G, et al. Noncovalent interactions with SUMO and ubiquitin orchestrate distinct functions of the SLX4 complex in genome maintenance. Mol Cell. 2015;57:108–22.

pubmed: 25533185 doi: 10.1016/j.molcel.2014.11.015

Papouli E, Chen S, Davies AA, Huttner D, Krejci L, Sung P, et al. Crosstalk between SUMO and ubiquitin on PCNA is mediated by recruitment of the helicase Srs2p. Mol cell. 2005;19:123–33.

pubmed: 15989970 doi: 10.1016/j.molcel.2005.06.001

Nagareddy B, Khan A, Kim H. Acetylation modulates the Fanconi anemia pathway by protecting FAAP20 from ubiquitin-mediated proteasomal degradation. J Biol Chem. 2020;295:13887–901.

pubmed: 32763975 pmcid: 7535921 doi: 10.1074/jbc.RA120.015288

Dufour C. How I manage patients with Fanconi anaemia. Br J Haematol. 2017;178:32–47.

pubmed: 28474441 doi: 10.1111/bjh.14615

Bogliolo M, Surrallés J. Fanconi anemia: a model disease for studies on human genetics and advanced therapeutics. Curr Opin Genet Dev. 2015;33:32–40.

pubmed: 26254775 doi: 10.1016/j.gde.2015.07.002

Alter BP, Giri N, Savage SA, Quint WG, de Koning MN, Schiffman M. Squamous cell carcinomas in patients with Fanconi anemia and dyskeratosis congenita: a search for human papillomavirus. Int J cancer. 2013;133:1513–5.

pubmed: 23558727 pmcid: 3707947 doi: 10.1002/ijc.28157

Carvalho JP, Dias ML, Carvalho FM, Del Pilar Estevez Diz M, Petito JW. Squamous cell vulvar carcinoma associated with Fanconi’s anemia: a case report. Int J Gynecol Cancer: Off J Int Gynecol Cancer Soc. 2002;12:220–2.

doi: 10.1136/ijgc-00009577-200203000-00015

Liu W, Palovcak A, Li F, Zafar A, Yuan F, Zhang Y. Fanconi anemia pathway as a prospective target for cancer intervention. Cell Biosci. 2020;10:39.

pubmed: 32190289 pmcid: 7075017 doi: 10.1186/s13578-020-00401-7