ATM-phosphorylated SPOP Contributes to 53BP1 Exclusion from Chromatin During DNA Replication

Overview

Journal Sci Adv

Specialties Biology
Science

Date 2021 Jun 19

PMID 34144977

Citations 19

Authors

Dejie Wang

Jian Ma

Maria Victoria Botuyan

Gaofeng Cui

Yuqian Yan

Donglin Ding

Yingke Zhou

Eugene W Krueger

Jiang Pei

Xiaosheng Wu

Liguo Wang

Huadong Pei

Mark A McNiven

Dingwei Ye

Georges Mer

Haojie Huang

Affiliations

Soon will be listed here.

Abstract

53BP1 activates nonhomologous end joining (NHEJ) and inhibits homologous recombination (HR) repair of DNA double-strand breaks (DSBs). Dissociation of 53BP1 from DSBs and consequent activation of HR, a less error-prone pathway than NHEJ, helps maintain genome integrity during DNA replication; however, the underlying mechanisms are not fully understood. Here, we demonstrate that E3 ubiquitin ligase SPOP promotes HR during S phase of the cell cycle by excluding 53BP1 from DSBs. In response to DNA damage, ATM kinase-catalyzed phosphorylation of SPOP causes a conformational change in SPOP, revealed by x-ray crystal structures, that stabilizes its interaction with 53BP1. 53BP1-bound SPOP induces polyubiquitination of 53BP1, eliciting 53BP1 extraction from chromatin by a valosin-containing protein/p97 segregase complex. Our work shows that SPOP facilitates HR repair over NHEJ during DNA replication by contributing to 53BP1 removal from chromatin. Cancer-derived SPOP mutations block SPOP interaction with 53BP1, inducing HR defects and chromosomal instability.

Citing Articles

DTX3L-mediated TIRR nuclear export and degradation regulates DNA repair pathway choice and PARP inhibitor sensitivity.

Ye Q, Ma J, Wang Z, Liu T, Wang B, Zhu L Nat Commun. 2024; 15(1):10596.

PMID: 39632881 PMC: 11618752. DOI: 10.1038/s41467-024-54978-5.

53BP1-the 'Pandora's box' of genome integrity.

Kilgas S, Swift M, Chowdhury D DNA Repair (Amst). 2024; 144:103779.

PMID: 39476547 PMC: 11611608. DOI: 10.1016/j.dnarep.2024.103779.

Phosphorylation of the DNA damage repair factor 53BP1 by ATM kinase controls neurodevelopmental programs in cortical brain organoids.

Lim B, Matsui Y, Jung S, Djekidel M, Qi W, Yuan Z PLoS Biol. 2024; 22(9):e3002760.

PMID: 39226322 PMC: 11398655. DOI: 10.1371/journal.pbio.3002760.

Effect of ubiquitin protease system on DNA damage response in prostate cancer (Review).

Lin Y, Jin X Exp Ther Med. 2023; 27(1):33.

PMID: 38125344 PMC: 10731405. DOI: 10.3892/etm.2023.12321.

The protein phosphatase EYA4 promotes homologous recombination (HR) through dephosphorylation of tyrosine 315 on RAD51.

de la Pena Avalos B, Paquet N, Tropee R, Coulombe Y, Palacios H, Leung J Nucleic Acids Res. 2023; 52(3):1173-1187.

PMID: 38084915 PMC: 10853800. DOI: 10.1093/nar/gkad1177.

References

Munoz I, Jowsey P, Toth R, Rouse J . Phospho-epitope binding by the BRCT domains of hPTIP controls multiple aspects of the cellular response to DNA damage. Nucleic Acids Res. 2007; 35(16):5312-22. PMC: 2018624. DOI: 10.1093/nar/gkm493. View

Pei H, Wu X, Liu T, Yu K, Jelinek D, Lou Z . The histone methyltransferase MMSET regulates class switch recombination. J Immunol. 2012; 190(2):756-63. PMC: 3775478. DOI: 10.4049/jimmunol.1201811. View

Bouchard J, Otero J, Scott D, Szulc E, Martin E, Sabri N . Cancer Mutations of the Tumor Suppressor SPOP Disrupt the Formation of Active, Phase-Separated Compartments. Mol Cell. 2018; 72(1):19-36.e8. PMC: 6179159. DOI: 10.1016/j.molcel.2018.08.027. View

Delaglio F, Grzesiek S, Vuister G, Zhu G, Pfeifer J, Bax A . NMRPipe: a multidimensional spectral processing system based on UNIX pipes. J Biomol NMR. 1995; 6(3):277-93. DOI: 10.1007/BF00197809. View

Meyer H, Weihl C . The VCP/p97 system at a glance: connecting cellular function to disease pathogenesis. J Cell Sci. 2014; 127(Pt 18):3877-83. PMC: 4163641. DOI: 10.1242/jcs.093831. View

Botuyan M, Cui G, Drane P, Oliveira C, Detappe A, Brault M . Mechanism of 53BP1 activity regulation by RNA-binding TIRR and a designer protein. Nat Struct Mol Biol. 2018; 25(7):591-600. PMC: 6045459. DOI: 10.1038/s41594-018-0083-z. View

Emsley P, Cowtan K . Coot: model-building tools for molecular graphics. Acta Crystallogr D Biol Crystallogr. 2004; 60(Pt 12 Pt 1):2126-32. DOI: 10.1107/S0907444904019158. View

Armenia J, Wankowicz S, Liu D, Gao J, Kundra R, Reznik E . The long tail of oncogenic drivers in prostate cancer. Nat Genet. 2018; 50(5):645-651. PMC: 6107367. DOI: 10.1038/s41588-018-0078-z. View

Dimitrova N, Chen Y, Spector D, de Lange T . 53BP1 promotes non-homologous end joining of telomeres by increasing chromatin mobility. Nature. 2008; 456(7221):524-8. PMC: 2613650. DOI: 10.1038/nature07433. View

10.

Zimmermann M, Lottersberger F, Buonomo S, Sfeir A, de Lange T . 53BP1 regulates DSB repair using Rif1 to control 5' end resection. Science. 2013; 339(6120):700-4. PMC: 3664841. DOI: 10.1126/science.1231573. View

11.

Acs K, Luijsterburg M, Ackermann L, Salomons F, Hoppe T, Dantuma N . The AAA-ATPase VCP/p97 promotes 53BP1 recruitment by removing L3MBTL1 from DNA double-strand breaks. Nat Struct Mol Biol. 2011; 18(12):1345-50. DOI: 10.1038/nsmb.2188. View

12.

Zhang D, Wang H, Sun M, Yang J, Zhang W, Han S . Speckle-type POZ protein, SPOP, is involved in the DNA damage response. Carcinogenesis. 2014; 35(8):1691-7. PMC: 4123640. DOI: 10.1093/carcin/bgu022. View

13.

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

14.

Gunn A, Stark J . I-SceI-based assays to examine distinct repair outcomes of mammalian chromosomal double strand breaks. Methods Mol Biol. 2012; 920:379-91. DOI: 10.1007/978-1-61779-998-3_27. View

15.

Geng C, He B, Xu L, Barbieri C, Eedunuri V, Chew S . Prostate cancer-associated mutations in speckle-type POZ protein (SPOP) regulate steroid receptor coactivator 3 protein turnover. Proc Natl Acad Sci U S A. 2013; 110(17):6997-7002. PMC: 3637757. DOI: 10.1073/pnas.1304502110. View

16.

Johnson B, Blevins R . NMR View: A computer program for the visualization and analysis of NMR data. J Biomol NMR. 2012; 4(5):603-14. DOI: 10.1007/BF00404272. View

17.

Hafsa N, Arndt D, Wishart D . CSI 3.0: a web server for identifying secondary and super-secondary structure in proteins using NMR chemical shifts. Nucleic Acids Res. 2015; 43(W1):W370-7. PMC: 4489240. DOI: 10.1093/nar/gkv494. View

18.

Ostertag M, Messias A, Sattler M, Popowicz G . The Structure of the SPOP-Pdx1 Interface Reveals Insights into the Phosphorylation-Dependent Binding Regulation. Structure. 2018; 27(2):327-334.e3. DOI: 10.1016/j.str.2018.10.005. View

19.

Jacquet K, Fradet-Turcotte A, Avvakumov N, Lambert J, Roques C, Pandita R . The TIP60 Complex Regulates Bivalent Chromatin Recognition by 53BP1 through Direct H4K20me Binding and H2AK15 Acetylation. Mol Cell. 2016; 62(3):409-421. PMC: 4887106. DOI: 10.1016/j.molcel.2016.03.031. View

20.

Cuella-Martin R, Oliveira C, Lockstone H, Snellenberg S, Grolmusova N, Chapman J . 53BP1 Integrates DNA Repair and p53-Dependent Cell Fate Decisions via Distinct Mechanisms. Mol Cell. 2016; 64(1):51-64. PMC: 5065530. DOI: 10.1016/j.molcel.2016.08.002. View