Remodeling of Interstrand Crosslink Proximal Replisomes Is Dependent on ATR, FANCM, and FANCD2

Overview

Journal Cell Rep

Publisher Cell Press

Specialties Biology
Cell Biology
Molecular Biology

Date 2019 May 9

PMID 31067464

Citations 37

Authors

Jing Huang

Jing Zhang

Marina A Bellani

Durga Pokharel

Julia Gichimu

Ryan C James

Himabindu Gali

Chen Ling

Zhijiang Yan

Dongyi Xu

Junjie Chen

Amom Ruhikanta Meetei

Lei Li

Weidong Wang

Michael M Seidman

Affiliations

Soon will be listed here.

Abstract

Eukaryotic replisomes are driven by the mini chromosome maintenance (MCM [M]) helicase complex, an offset ring locked around the template for leading strand synthesis by CDC45 (C) and GINS (G) proteins. Although the CDC45 MCM GINS (CMG) structure implies that interstrand crosslinks (ICLs) are absolute blocks to replisomes, recent studies indicate that cells can restart DNA synthesis on the side of the ICL distal to the initial encounter. Here, we report that restart requires ATR and is promoted by FANCD2 and phosphorylated FANCM. Following introduction of genomic ICLs and dependent on ATR and FANCD2 but not on the Fanconi anemia core proteins or FAAP24, FANCM binds the replisome complex, with concomitant release of the GINS proteins. In situ analysis of replisomes proximal to ICLs confirms the ATR-dependent release of GINS proteins while CDC45 is retained on the remodeled replisome. The results demonstrate the plasticity of CMG composition in response to replication stress.

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References

Charych D, Coyne M, Yabannavar A, Narberes J, Chow S, Wallroth M . Inhibition of Cdc7/Dbf4 kinase activity affects specific phosphorylation sites on MCM2 in cancer cells. J Cell Biochem. 2008; 104(3):1075-86. DOI: 10.1002/jcb.21698. View

Saldivar J, Cortez D, Cimprich K . The essential kinase ATR: ensuring faithful duplication of a challenging genome. Nat Rev Mol Cell Biol. 2017; 18(10):622-636. PMC: 5796526. DOI: 10.1038/nrm.2017.67. View

Singh T, Ali A, Paramasivam M, Pradhan A, Wahengbam K, Seidman M . ATR-dependent phosphorylation of FANCM at serine 1045 is essential for FANCM functions. Cancer Res. 2013; 73(14):4300-10. PMC: 3732194. DOI: 10.1158/0008-5472.CAN-12-3976. View

Zellweger R, Dalcher D, Mutreja K, Berti M, Schmid J, Herrador R . Rad51-mediated replication fork reversal is a global response to genotoxic treatments in human cells. J Cell Biol. 2015; 208(5):563-79. PMC: 4347635. DOI: 10.1083/jcb.201406099. View

Costa A, Ilves I, Tamberg N, Petojevic T, Nogales E, Botchan M . The structural basis for MCM2-7 helicase activation by GINS and Cdc45. Nat Struct Mol Biol. 2011; 18(4):471-7. PMC: 4184033. DOI: 10.1038/nsmb.2004. View

Weber C, Salazar E, Stewart S, Thompson L . Molecular cloning and biological characterization of a human gene, ERCC2, that corrects the nucleotide excision repair defect in CHO UV5 cells. Mol Cell Biol. 1988; 8(3):1137-46. PMC: 363258. DOI: 10.1128/mcb.8.3.1137-1146.1988. View

Mijic S, Zellweger R, Chappidi N, Berti M, Jacobs K, Mutreja K . Replication fork reversal triggers fork degradation in BRCA2-defective cells. Nat Commun. 2017; 8(1):859. PMC: 5643541. DOI: 10.1038/s41467-017-01164-5. View

Georgescu R, Yuan Z, Bai L, de Luna Almeida Santos R, Sun J, Zhang D . Structure of eukaryotic CMG helicase at a replication fork and implications to replisome architecture and origin initiation. Proc Natl Acad Sci U S A. 2017; 114(5):E697-E706. PMC: 5293012. DOI: 10.1073/pnas.1620500114. View

Price N, Li L, Gates K, Wang Y . Replication and repair of a reduced 2΄-deoxyguanosine-abasic site interstrand cross-link in human cells. Nucleic Acids Res. 2017; 45(11):6486-6493. PMC: 5499640. DOI: 10.1093/nar/gkx266. View

10.

Wang Y, Leung J, Jiang Y, Lowery M, Do H, Vasquez K . FANCM and FAAP24 maintain genome stability via cooperative as well as unique functions. Mol Cell. 2013; 49(5):997-1009. PMC: 3595374. DOI: 10.1016/j.molcel.2012.12.010. View

11.

Meetei A, Medhurst A, Ling C, Xue Y, Singh T, Bier P . A human ortholog of archaeal DNA repair protein Hef is defective in Fanconi anemia complementation group M. Nat Genet. 2005; 37(9):958-63. PMC: 2704909. DOI: 10.1038/ng1626. View

12.

Bochman M, Schwacha A . The Mcm complex: unwinding the mechanism of a replicative helicase. Microbiol Mol Biol Rev. 2009; 73(4):652-83. PMC: 2786579. DOI: 10.1128/MMBR.00019-09. View

13.

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

14.

Tacconi E, Lai X, Folio C, Porru M, Zonderland G, Badie S . BRCA1 and BRCA2 tumor suppressors protect against endogenous acetaldehyde toxicity. EMBO Mol Med. 2017; 9(10):1398-1414. PMC: 5623864. DOI: 10.15252/emmm.201607446. View

15.

Semlow D, Zhang J, Budzowska M, Drohat A, Walter J . Replication-Dependent Unhooking of DNA Interstrand Cross-Links by the NEIL3 Glycosylase. Cell. 2016; 167(2):498-511.e14. PMC: 5237264. DOI: 10.1016/j.cell.2016.09.008. View

16.

Abid Ali F, Renault L, Gannon J, Gahlon H, Kotecha A, Zhou J . Cryo-EM structures of the eukaryotic replicative helicase bound to a translocation substrate. Nat Commun. 2016; 7:10708. PMC: 4759635. DOI: 10.1038/ncomms10708. View

17.

Matsuoka S, Ballif B, Smogorzewska A, McDonald 3rd E, Hurov K, Luo J . ATM and ATR substrate analysis reveals extensive protein networks responsive to DNA damage. Science. 2007; 316(5828):1160-6. DOI: 10.1126/science.1140321. View

18.

Rolseth V, Luna L, Olsen A, Suganthan R, Scheffler K, Neurauter C . No cancer predisposition or increased spontaneous mutation frequencies in NEIL DNA glycosylases-deficient mice. Sci Rep. 2017; 7(1):4384. PMC: 5491499. DOI: 10.1038/s41598-017-04472-4. View

19.

Thompson E, Yeo J, Lee E, Kan Y, Raghunandan M, Wiek C . FANCI and FANCD2 have common as well as independent functions during the cellular replication stress response. Nucleic Acids Res. 2017; 45(20):11837-11857. PMC: 5714191. DOI: 10.1093/nar/gkx847. View

20.

Wiegant W, Overmeer R, Godthelp B, van Buul P, Zdzienicka M . Chinese hamster cell mutant, V-C8, a model for analysis of Brca2 function. Mutat Res. 2006; 600(1-2):79-88. DOI: 10.1016/j.mrfmmm.2006.03.001. View