ATM-ESCO2-SMC3 Axis Promotes 53BP1 Recruitment in Response to DNA Damage and Safeguards Genome Integrity by Stabilizing Cohesin Complex

Overview

Journal Nucleic Acids Res

Publisher Oxford University Press

Specialty Biochemistry

Date 2023 Jun 28

PMID 37377435

Authors

Jianfeng Fu

Siru Zhou

Huilin Xu

Liming Liao

Hui Shen

Peng Du

Xiaofeng Zheng

Affiliations

Soon will be listed here.

Abstract

53BP1 is primarily known as a key regulator in DNA double-strand break (DSB) repair. However, the mechanism of DSB-triggered cohesin modification-modulated chromatin structure on the recruitment of 53BP1 remains largely elusive. Here, we identified acetyltransferase ESCO2 as a regulator for DSB-induced cohesin-dependent chromatin structure dynamics, which promotes 53BP1 recruitment. Mechanistically, in response to DNA damage, ATM phosphorylates ESCO2 S196 and T233. MDC1 recognizes phosphorylated ESCO2 and recruits ESCO2 to DSB sites. ESCO2-mediated acetylation of SMC3 stabilizes cohesin complex conformation and regulates the chromatin structure at DSB breaks, which is essential for the recruitment of 53BP1 and the formation of 53BP1 microdomains. Furthermore, depletion of ESCO2 in both colorectal cancer cells and xenografted nude mice sensitizes cancer cells to chemotherapeutic drugs. Collectively, our results reveal a molecular mechanism for the ATM-ESCO2-SMC3 axis in DSB repair and genome integrity maintenance with a vital role in chemotherapy response in colorectal cancer.

Citing Articles

Redox regulation: mechanisms, biology and therapeutic targets in diseases.

Li B, Ming H, Qin S, Nice E, Dong J, Du Z Signal Transduct Target Ther. 2025; 10(1):72.

PMID: 40050273 PMC: 11885647. DOI: 10.1038/s41392-024-02095-6.

Single-cell RNA sequencing of the carotid artery and femoral artery of rats exposed to hindlimb unloading.

Li C, Pan Y, Wang Y, Li X, Tie Y, Li S Cell Mol Life Sci. 2025; 82(1):50.

PMID: 39833543 PMC: 11747068. DOI: 10.1007/s00018-024-05572-x.

Association Between the rs13306703 and rs8192288 Variants of the Gene and Breast Cancer and an In Silico Analysis of the Variants' Impact.

Gallegos-Arreola M, Garibaldi-Rios A, Magana-Torres M, Figuera L, Gomez-Meda B, Zuniga-Gonzalez G Diseases. 2024; 12(11).

PMID: 39589950 PMC: 11592857. DOI: 10.3390/diseases12110276.

Cohesin complex oligomerization maintains end-tethering at DNA double-strand breaks.

Phipps J, Toulouze M, Ducrot C, Costa R, Brocas C, Dubrana K Nat Cell Biol. 2024; 27(1):118-129.

PMID: 39482358 PMC: 11735392. DOI: 10.1038/s41556-024-01552-2.

Key molecular DNA damage responses of human cells to radiation.

Zhang C, Liu J, Wu J, Ranjan K, Cui X, Wang X Front Cell Dev Biol. 2024; 12:1422520.

PMID: 39050891 PMC: 11266142. DOI: 10.3389/fcell.2024.1422520.

References

Iacovoni J, Caron P, Lassadi I, Nicolas E, Massip L, Trouche D . High-resolution profiling of gammaH2AX around DNA double strand breaks in the mammalian genome. EMBO J. 2010; 29(8):1446-57. PMC: 2868577. DOI: 10.1038/emboj.2010.38. View

Eaton J, Zidovska A . Structural and Dynamical Signatures of Local DNA Damage in Live Cells. Biophys J. 2019; 118(9):2168-2180. PMC: 7202935. DOI: 10.1016/j.bpj.2019.10.042. View

Tubbs A, Nussenzweig A . Endogenous DNA Damage as a Source of Genomic Instability in Cancer. Cell. 2017; 168(4):644-656. PMC: 6591730. DOI: 10.1016/j.cell.2017.01.002. View

Chapman J, Taylor M, Boulton S . Playing the end game: DNA double-strand break repair pathway choice. Mol Cell. 2012; 47(4):497-510. DOI: 10.1016/j.molcel.2012.07.029. View

Samadder P, Aithal R, Belan O, Krejci L . Cancer TARGETases: DSB repair as a pharmacological target. Pharmacol Ther. 2016; 161:111-131. DOI: 10.1016/j.pharmthera.2016.02.007. View

Stewart G, Wang B, Bignell C, Taylor A, Elledge S . MDC1 is a mediator of the mammalian DNA damage checkpoint. Nature. 2003; 421(6926):961-6. DOI: 10.1038/nature01446. View

Mfarej M, Skibbens R . Genetically induced redox stress occurs in a yeast model for Roberts syndrome. G3 (Bethesda). 2021; 12(2). PMC: 9210317. DOI: 10.1093/g3journal/jkab426. View

Piazza A, Bordelet H, Dumont A, Thierry A, Savocco J, Girard F . Cohesin regulates homology search during recombinational DNA repair. Nat Cell Biol. 2021; 23(11):1176-1186. DOI: 10.1038/s41556-021-00783-x. View

Zuin J, Dixon J, van der Reijden M, Ye Z, Kolovos P, Brouwer R . Cohesin and CTCF differentially affect chromatin architecture and gene expression in human cells. Proc Natl Acad Sci U S A. 2013; 111(3):996-1001. PMC: 3903193. DOI: 10.1073/pnas.1317788111. View

10.

Ochs F, Karemore G, Miron E, Brown J, Sedlackova H, Rask M . Stabilization of chromatin topology safeguards genome integrity. Nature. 2019; 574(7779):571-574. DOI: 10.1038/s41586-019-1659-4. View

11.

Kilic S, Lezaja A, Gatti M, Bianco E, Michelena J, Imhof R . Phase separation of 53BP1 determines liquid-like behavior of DNA repair compartments. EMBO J. 2019; 38(16):e101379. PMC: 6694294. DOI: 10.15252/embj.2018101379. View

12.

Vega H, Waisfisz Q, Gordillo M, Sakai N, Yanagihara I, Yamada M . Roberts syndrome is caused by mutations in ESCO2, a human homolog of yeast ECO1 that is essential for the establishment of sister chromatid cohesion. Nat Genet. 2005; 37(5):468-70. DOI: 10.1038/ng1548. View

13.

Gordillo M, Vega H, Trainer A, Hou F, Sakai N, Luque R . The molecular mechanism underlying Roberts syndrome involves loss of ESCO2 acetyltransferase activity. Hum Mol Genet. 2008; 17(14):2172-80. DOI: 10.1093/hmg/ddn116. View

14.

Nordlinger B, Sorbye H, Glimelius B, Poston G, Schlag P, Rougier P . Perioperative chemotherapy with FOLFOX4 and surgery versus surgery alone for resectable liver metastases from colorectal cancer (EORTC Intergroup trial 40983): a randomised controlled trial. Lancet. 2008; 371(9617):1007-16. PMC: 2277487. DOI: 10.1016/S0140-6736(08)60455-9. View

15.

Blackford A, Jackson S . ATM, ATR, and DNA-PK: The Trinity at the Heart of the DNA Damage Response. Mol Cell. 2017; 66(6):801-817. DOI: 10.1016/j.molcel.2017.05.015. View

16.

Zhao B, Rothenberg E, Ramsden D, Lieber M . The molecular basis and disease relevance of non-homologous DNA end joining. Nat Rev Mol Cell Biol. 2020; 21(12):765-781. PMC: 8063501. DOI: 10.1038/s41580-020-00297-8. View

17.

Yang C, Zang W, Tang Z, Ji Y, Xu R, Yang Y . A20/TNFAIP3 Regulates the DNA Damage Response and Mediates Tumor Cell Resistance to DNA-Damaging Therapy. Cancer Res. 2017; 78(4):1069-1082. DOI: 10.1158/0008-5472.CAN-17-2143. View

18.

Fattah F, Lee E, Weisensel N, Wang Y, Lichter N, Hendrickson E . Ku regulates the non-homologous end joining pathway choice of DNA double-strand break repair in human somatic cells. PLoS Genet. 2010; 6(2):e1000855. PMC: 2829059. DOI: 10.1371/journal.pgen.1000855. View

19.

Srinivas U, Tan B, Vellayappan B, Jeyasekharan A . ROS and the DNA damage response in cancer. Redox Biol. 2019; 25:101084. PMC: 6859528. DOI: 10.1016/j.redox.2018.101084. View

20.

Zhu D, Xu R, Huang X, Tang Z, Tian Y, Zhang J . Deubiquitinating enzyme OTUB1 promotes cancer cell immunosuppression via preventing ER-associated degradation of immune checkpoint protein PD-L1. Cell Death Differ. 2020; 28(6):1773-1789. PMC: 8184985. DOI: 10.1038/s41418-020-00700-z. View