UBC13-Mediated Ubiquitin Signaling Promotes Removal of Blocking Adducts from DNA Double-Strand Breaks

Overview

Journal iScience

Publisher Cell Press

Date 2020 Apr 14

PMID 32283528

Citations 6

Authors

Remi Akagawa

Hai Thanh Trinh

Liton Kumar Saha

Masataka Tsuda

Kouji Hirota

Shintaro Yamada

Atsushi Shibata

Masato T Kanemaki

Shinichiro Nakada

Shunichi Takeda

Hiroyuki Sasanuma

Affiliations

Soon will be listed here.

Abstract

Chemical modifications and adducts at DNA double-strand break (DSB) ends must be cleaned before re-joining by non-homologous end-joining (NHEJ). MRE11 nuclease is essential for efficient removal of Topoisomerase II (TOP2)-DNA adducts from TOP2 poison-induced DSBs. However, mechanisms in MRE11 recruitment to DSB sites in G phase remain poorly understood. Here, we report that TOP2-DNA adducts are expeditiously removed through UBC13-mediated polyubiquitination, which promotes DSB resection in G phase. We found that this ubiquitin signaling is required for efficient recruitment of MRE11 onto DSB sites in G by facilitating localization of RAP80 and BRCA1 to DSB sites and complex formation between BRCA1 and MRE11 at DSB sites. UBC13 and MRE11 are dispensable for restriction-enzyme-induced "clean" DSBs repair but responsible for over 50% and 70% of NHEJ-dependent repair of γ-ray-induced "dirty" DSBs, respectively. In conclusion, ubiquitin signaling promotes nucleolytic removal of DSB blocking adducts by MRE11 before NHEJ.

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References

Yamamoto M, Okamoto T, Takeda K, Sato S, Sanjo H, Uematsu S . Key function for the Ubc13 E2 ubiquitin-conjugating enzyme in immune receptor signaling. Nat Immunol. 2006; 7(9):962-70. DOI: 10.1038/ni1367. View

Wang B, Matsuoka S, Ballif B, Zhang D, Smogorzewska A, Gygi S . Abraxas and RAP80 form a BRCA1 protein complex required for the DNA damage response. Science. 2007; 316(5828):1194-8. PMC: 3573690. DOI: 10.1126/science.1139476. View

Gupta R, Somyajit K, Narita T, Maskey E, Stanlie A, Kremer M . DNA Repair Network Analysis Reveals Shieldin as a Key Regulator of NHEJ and PARP Inhibitor Sensitivity. Cell. 2018; 173(4):972-988.e23. PMC: 8108093. DOI: 10.1016/j.cell.2018.03.050. View

Anand R, Jasrotia A, Bundschuh D, Howard S, Ranjha L, Stucki M . NBS1 promotes the endonuclease activity of the MRE11-RAD50 complex by sensing CtIP phosphorylation. EMBO J. 2019; 38(7). PMC: 6443204. DOI: 10.15252/embj.2018101005. View

Biehs R, Steinlage M, Barton O, Juhasz S, Kunzel J, Spies J . DNA Double-Strand Break Resection Occurs during Non-homologous End Joining in G1 but Is Distinct from Resection during Homologous Recombination. Mol Cell. 2017; 65(4):671-684.e5. PMC: 5316416. DOI: 10.1016/j.molcel.2016.12.016. View

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

Shrivastav M, De Haro L, Nickoloff J . Regulation of DNA double-strand break repair pathway choice. Cell Res. 2007; 18(1):134-47. DOI: 10.1038/cr.2007.111. View

Moynahan M, Jasin M . Mitotic homologous recombination maintains genomic stability and suppresses tumorigenesis. Nat Rev Mol Cell Biol. 2010; 11(3):196-207. PMC: 3261768. DOI: 10.1038/nrm2851. View

ODriscoll M, Jeggo P . The role of double-strand break repair - insights from human genetics. Nat Rev Genet. 2005; 7(1):45-54. DOI: 10.1038/nrg1746. View

10.

Nakada S . Opposing roles of RNF8/RNF168 and deubiquitinating enzymes in ubiquitination-dependent DNA double-strand break response signaling and DNA-repair pathway choice. J Radiat Res. 2016; 57 Suppl 1:i33-i40. PMC: 4990112. DOI: 10.1093/jrr/rrw027. View

11.

Simsek D, Furda A, Gao Y, Artus J, Brunet E, Hadjantonakis A . Crucial role for DNA ligase III in mitochondria but not in Xrcc1-dependent repair. Nature. 2011; 471(7337):245-8. PMC: 3261757. DOI: 10.1038/nature09794. View

12.

Asaithamby A, Hu B, Chen D . Unrepaired clustered DNA lesions induce chromosome breakage in human cells. Proc Natl Acad Sci U S A. 2011; 108(20):8293-8. PMC: 3100920. DOI: 10.1073/pnas.1016045108. View

13.

Roques C, Coulombe Y, Delannoy M, Vignard J, Grossi S, Brodeur I . MRE11-RAD50-NBS1 is a critical regulator of FANCD2 stability and function during DNA double-strand break repair. EMBO J. 2009; 28(16):2400-13. PMC: 2735166. DOI: 10.1038/emboj.2009.193. View

14.

Deshpande R, Lee J, Arora S, Paull T . Nbs1 Converts the Human Mre11/Rad50 Nuclease Complex into an Endo/Exonuclease Machine Specific for Protein-DNA Adducts. Mol Cell. 2016; 64(3):593-606. DOI: 10.1016/j.molcel.2016.10.010. View

15.

Jachimowicz R, Beleggia F, Isensee J, Velpula B, Goergens J, Bustos M . UBQLN4 Represses Homologous Recombination and Is Overexpressed in Aggressive Tumors. Cell. 2019; 176(3):505-519.e22. DOI: 10.1016/j.cell.2018.11.024. View

16.

Woodbine L, Brunton H, Goodarzi A, Shibata A, Jeggo P . Endogenously induced DNA double strand breaks arise in heterochromatic DNA regions and require ataxia telangiectasia mutated and Artemis for their repair. Nucleic Acids Res. 2011; 39(16):6986-97. PMC: 3167608. DOI: 10.1093/nar/gkr331. View

17.

Lee K, Swan R, Sondka Z, Padget K, Cowell I, Austin C . Effect of TDP2 on the Level of TOP2-DNA Complexes and SUMOylated TOP2-DNA Complexes. Int J Mol Sci. 2018; 19(7). PMC: 6073685. DOI: 10.3390/ijms19072056. View

18.

Jeggo P, Geuting V, Lobrich M . The role of homologous recombination in radiation-induced double-strand break repair. Radiother Oncol. 2011; 101(1):7-12. DOI: 10.1016/j.radonc.2011.06.019. View

19.

Moreau S, Ferguson J, Symington L . The nuclease activity of Mre11 is required for meiosis but not for mating type switching, end joining, or telomere maintenance. Mol Cell Biol. 1998; 19(1):556-66. PMC: 83913. DOI: 10.1128/MCB.19.1.556. View

20.

Falck J, Forment J, Coates J, Mistrik M, Lukas J, Bartek J . CDK targeting of NBS1 promotes DNA-end resection, replication restart and homologous recombination. EMBO Rep. 2012; 13(6):561-8. PMC: 3367243. DOI: 10.1038/embor.2012.58. View