Processing of DNA Double-Strand Breaks by the MRX Complex in a Chromatin Context

Overview

Journal Front Mol Biosci

Specialty Biology

Date 2019 Jun 25

PMID 31231660

Citations 22

Authors

Erika Casari

Carlo Rinaldi

Antonio Marsella

Marco Gnugnoli

Chiara Vittoria Colombo

Diego Bonetti

Maria Pia Longhese

Affiliations

Soon will be listed here.

Abstract

DNA double-strand breaks (DSBs) are highly cytotoxic lesions that must be repaired to ensure genomic stability and avoid cell death. The cellular response to DSBs is initiated by the evolutionarily conserved Mre11-Rad50-Xrs2/NBS1 (MRX/MRN) complex that has structural and catalytic functions. Furthermore, it is responsible for DSB signaling through the activation of the checkpoint kinase Tel1/ATM. Here, we review functions and regulation of the MRX/MRN complex in DSB processing in a chromatin context, as well as its interplay with Tel1/ATM.

Citing Articles

Rev7 promotes non-homologous end-joining by blocking Mre11 nuclease and Rad50's ATPase activities and homologous recombination.

Badugu S, Dhyani K, Thakur M, Muniyappa K Elife. 2024; 13.

PMID: 39630591 PMC: 11616998. DOI: 10.7554/eLife.96933.

Genetic tools for metabolic engineering of .

Wu X, Cai P, Yao L, Zhou Y Eng Microbiol. 2024; 3(4):100094.

PMID: 39628915 PMC: 11611016. DOI: 10.1016/j.engmic.2023.100094.

HLTF disrupts Cas9-DNA post-cleavage complexes to allow DNA break processing.

Reginato G, Dello Stritto M, Wang Y, Hao J, Pavani R, Schmitz M Nat Commun. 2024; 15(1):5789.

PMID: 38987539 PMC: 11237066. DOI: 10.1038/s41467-024-50080-y.

An outlook to sophisticated technologies and novel developments for metabolic regulation in the expression system.

Wu Y, Feng S, Sun Z, Hu Y, Jia X, Zeng B Front Bioeng Biotechnol. 2023; 11:1249841.

PMID: 37869712 PMC: 10586203. DOI: 10.3389/fbioe.2023.1249841.

Drug Discovery Targeting Post-Translational Modifications in Response to DNA Damages Induced by Space Radiation.

Xie D, Huang Q, Zhou P Int J Mol Sci. 2023; 24(8).

PMID: 37108815 PMC: 10142602. DOI: 10.3390/ijms24087656.

References

Liu Y, Sung S, Kim Y, Li F, Gwon G, Jo A . ATP-dependent DNA binding, unwinding, and resection by the Mre11/Rad50 complex. EMBO J. 2016; 35(7):743-58. PMC: 4818763. DOI: 10.15252/embj.201592462. View

Levikova M, Pinto C, Cejka P . The motor activity of DNA2 functions as an ssDNA translocase to promote DNA end resection. Genes Dev. 2017; 31(5):493-502. PMC: 5393063. DOI: 10.1101/gad.295196.116. View

Chai B, Huang J, Cairns B, Laurent B . Distinct roles for the RSC and Swi/Snf ATP-dependent chromatin remodelers in DNA double-strand break repair. Genes Dev. 2005; 19(14):1656-61. PMC: 1176001. DOI: 10.1101/gad.1273105. View

Kowalczykowski S . An Overview of the Molecular Mechanisms of Recombinational DNA Repair. Cold Spring Harb Perspect Biol. 2015; 7(11). PMC: 4632670. DOI: 10.1101/cshperspect.a016410. View

Kao H, Campbell J, Bambara R . Dna2p helicase/nuclease is a tracking protein, like FEN1, for flap cleavage during Okazaki fragment maturation. J Biol Chem. 2004; 279(49):50840-9. DOI: 10.1074/jbc.M409231200. View

You Z, Chahwan C, Bailis J, Hunter T, Russell P . ATM activation and its recruitment to damaged DNA require binding to the C terminus of Nbs1. Mol Cell Biol. 2005; 25(13):5363-79. PMC: 1156989. DOI: 10.1128/MCB.25.13.5363-5379.2005. View

Sturzenegger A, Burdova K, Kanagaraj R, Levikova M, Pinto C, Cejka P . DNA2 cooperates with the WRN and BLM RecQ helicases to mediate long-range DNA end resection in human cells. J Biol Chem. 2014; 289(39):27314-27326. PMC: 4175362. DOI: 10.1074/jbc.M114.578823. View

Mehta A, Haber J . Sources of DNA double-strand breaks and models of recombinational DNA repair. Cold Spring Harb Perspect Biol. 2014; 6(9):a016428. PMC: 4142968. DOI: 10.1101/cshperspect.a016428. View

Deshpande R, Williams G, Limbo O, Williams R, Kuhnlein J, Lee J . ATP-driven Rad50 conformations regulate DNA tethering, end resection, and ATM checkpoint signaling. EMBO J. 2014; 33(5):482-500. PMC: 3989629. DOI: 10.1002/embj.201386100. View

10.

Costelloe T, Louge R, Tomimatsu N, Mukherjee B, Martini E, Khadaroo B . The yeast Fun30 and human SMARCAD1 chromatin remodellers promote DNA end resection. Nature. 2012; 489(7417):581-4. PMC: 3493121. DOI: 10.1038/nature11353. View

11.

Usui T, Ohta T, Oshiumi H, Tomizawa J, Ogawa H, Ogawa T . Complex formation and functional versatility of Mre11 of budding yeast in recombination. Cell. 1998; 95(5):705-16. DOI: 10.1016/s0092-8674(00)81640-2. View

12.

Lim H, Kim J, Park Y, Gwon G, Cho Y . Crystal structure of the Mre11-Rad50-ATPγS complex: understanding the interplay between Mre11 and Rad50. Genes Dev. 2011; 25(10):1091-104. PMC: 3093124. DOI: 10.1101/gad.2037811. View

13.

Lee J, Mand M, Deshpande R, Kinoshita E, Yang S, Wyman C . Ataxia telangiectasia-mutated (ATM) kinase activity is regulated by ATP-driven conformational changes in the Mre11/Rad50/Nbs1 (MRN) complex. J Biol Chem. 2013; 288(18):12840-51. PMC: 3642328. DOI: 10.1074/jbc.M113.460378. View

14.

ODriscoll M . Diseases associated with defective responses to DNA damage. Cold Spring Harb Perspect Biol. 2012; 4(12). PMC: 3504433. DOI: 10.1101/cshperspect.a012773. View

15.

Levy D, Blackburn E . Counting of Rif1p and Rif2p on Saccharomyces cerevisiae telomeres regulates telomere length. Mol Cell Biol. 2004; 24(24):10857-67. PMC: 533994. DOI: 10.1128/MCB.24.24.10857-10867.2004. View

16.

Kari V, Mansour W, Raul S, Baumgart S, Mund A, Grade M . Loss of CHD1 causes DNA repair defects and enhances prostate cancer therapeutic responsiveness. EMBO Rep. 2016; 17(11):1609-1623. PMC: 5090703. DOI: 10.15252/embr.201642352. View

17.

Syed A, Tainer J . The MRE11-RAD50-NBS1 Complex Conducts the Orchestration of Damage Signaling and Outcomes to Stress in DNA Replication and Repair. Annu Rev Biochem. 2018; 87:263-294. PMC: 6076887. DOI: 10.1146/annurev-biochem-062917-012415. View

18.

Arya R, Bassing C . V(D)J Recombination Exploits DNA Damage Responses to Promote Immunity. Trends Genet. 2017; 33(7):479-489. PMC: 5499712. DOI: 10.1016/j.tig.2017.04.006. View

19.

Myler L, Gallardo I, Soniat M, Deshpande R, Gonzalez X, Kim Y . Single-Molecule Imaging Reveals How Mre11-Rad50-Nbs1 Initiates DNA Break Repair. Mol Cell. 2017; 67(5):891-898.e4. PMC: 5609712. DOI: 10.1016/j.molcel.2017.08.002. View

20.

Gobbini E, Cesena D, Galbiati A, Lockhart A, Longhese M . Interplays between ATM/Tel1 and ATR/Mec1 in sensing and signaling DNA double-strand breaks. DNA Repair (Amst). 2013; 12(10):791-9. DOI: 10.1016/j.dnarep.2013.07.009. View