Cohesin Regulates Homology Search During Recombinational DNA Repair

Overview

Journal Nat Cell Biol

Specialty Cell Biology

Date 2021 Nov 9

PMID 34750581

Citations 30

Authors

Aurele Piazza

Helene Bordelet

Agnes Dumont

Agnes Thierry

Jerome Savocco

Fabien Girard

Romain Koszul

Affiliations

Soon will be listed here.

Abstract

Homologous recombination repairs DNA double-strand breaks (DSB) using an intact dsDNA molecule as a template. It entails a homology search step, carried out along a conserved RecA/Rad51-ssDNA filament assembled on each DSB end. Whether, how and to what extent a DSB impacts chromatin folding, and how this (re)organization in turns influences the homology search process, remain ill-defined. Here we characterize two layers of spatial chromatin reorganization following DSB formation in Saccharomyces cerevisiae. Although cohesin folds chromosomes into cohesive arrays of ~20-kb-long chromatin loops as cells arrest in G2/M, the DSB-flanking regions interact locally in a resection- and 9-1-1 clamp-dependent manner, independently of cohesin, Mec1, Rad52 and Rad51. This local structure blocks cohesin progression, constraining the DSB region at the base of a loop. Functionally, cohesin promotes DSB-dsDNA interactions and donor identification in cis, while inhibiting them in trans. This study identifies multiple direct and indirect ways by which cohesin regulates homology search during recombinational DNA repair.

Citing Articles

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References

Renkawitz J, Lademann C, Jentsch S . Mechanisms and principles of homology search during recombination. Nat Rev Mol Cell Biol. 2014; 15(6):369-83. DOI: 10.1038/nrm3805. View

Bell J, Kowalczykowski S . RecA: Regulation and Mechanism of a Molecular Search Engine. Trends Biochem Sci. 2016; 41(6):491-507. PMC: 4892382. DOI: 10.1016/j.tibs.2016.04.002. View

Forget A, Kowalczykowski S . Single-molecule imaging of DNA pairing by RecA reveals a three-dimensional homology search. Nature. 2012; 482(7385):423-7. PMC: 3288143. DOI: 10.1038/nature10782. View

Yang H, Zhou C, Dhar A, Pavletich N . Mechanism of strand exchange from RecA-DNA synaptic and D-loop structures. Nature. 2020; 586(7831):801-806. PMC: 8366275. DOI: 10.1038/s41586-020-2820-9. View

Burgess S, Kleckner N . Collisions between yeast chromosomal loci in vivo are governed by three layers of organization. Genes Dev. 1999; 13(14):1871-83. PMC: 316882. DOI: 10.1101/gad.13.14.1871. View

Agmon N, Liefshitz B, Zimmer C, Fabre E, Kupiec M . Effect of nuclear architecture on the efficiency of double-strand break repair. Nat Cell Biol. 2013; 15(6):694-9. DOI: 10.1038/ncb2745. View

Lee C, Wang R, Chang H, Capurso D, Segal M, Haber J . Chromosome position determines the success of double-strand break repair. Proc Natl Acad Sci U S A. 2015; 113(2):E146-54. PMC: 4720327. DOI: 10.1073/pnas.1523660113. View

Batte A, Brocas C, Bordelet H, Hocher A, Ruault M, Adjiri A . Recombination at subtelomeres is regulated by physical distance, double-strand break resection and chromatin status. EMBO J. 2017; 36(17):2609-2625. PMC: 5579382. DOI: 10.15252/embj.201796631. View

Arnould C, Legube G . The Secret Life of Chromosome Loops upon DNA Double-Strand Break. J Mol Biol. 2019; 432(3):724-736. PMC: 7057266. DOI: 10.1016/j.jmb.2019.07.036. View

10.

Sanders J, Freeman T, Xu Y, Golloshi R, Stallard M, Hill A . Radiation-induced DNA damage and repair effects on 3D genome organization. Nat Commun. 2020; 11(1):6178. PMC: 7710719. DOI: 10.1038/s41467-020-20047-w. View

11.

Waterman D, Haber J, Smolka M . Checkpoint Responses to DNA Double-Strand Breaks. Annu Rev Biochem. 2020; 89:103-133. PMC: 7311309. DOI: 10.1146/annurev-biochem-011520-104722. View

12.

Arnould C, Rocher V, Finoux A, Clouaire T, Li K, Zhou F . Loop extrusion as a mechanism for formation of DNA damage repair foci. Nature. 2021; 590(7847):660-665. PMC: 7116834. DOI: 10.1038/s41586-021-03193-z. View

13.

Strom L, Lindroos H, Shirahige K, Sjogren C . Postreplicative recruitment of cohesin to double-strand breaks is required for DNA repair. Mol Cell. 2004; 16(6):1003-15. DOI: 10.1016/j.molcel.2004.11.026. View

14.

Heidinger-Pauli J, Unal E, Guacci V, Koshland D . The kleisin subunit of cohesin dictates damage-induced cohesion. Mol Cell. 2008; 31(1):47-56. DOI: 10.1016/j.molcel.2008.06.005. View

15.

Unal E, Arbel-Eden A, Sattler U, Shroff R, Lichten M, Haber J . DNA damage response pathway uses histone modification to assemble a double-strand break-specific cohesin domain. Mol Cell. 2004; 16(6):991-1002. DOI: 10.1016/j.molcel.2004.11.027. View

16.

Unal E, Heidinger-Pauli J, Koshland D . DNA double-strand breaks trigger genome-wide sister-chromatid cohesion through Eco1 (Ctf7). Science. 2007; 317(5835):245-8. DOI: 10.1126/science.1140637. View

17.

Unal E, Heidinger-Pauli J, Kim W, Guacci V, Onn I, Gygi S . A molecular determinant for the establishment of sister chromatid cohesion. Science. 2008; 321(5888):566-9. DOI: 10.1126/science.1157880. View

18.

Kadyk L, Hartwell L . Sister chromatids are preferred over homologs as substrates for recombinational repair in Saccharomyces cerevisiae. Genetics. 1992; 132(2):387-402. PMC: 1205144. DOI: 10.1093/genetics/132.2.387. View

19.

Birkenbihl R, Subramani S . Cloning and characterization of rad21 an essential gene of Schizosaccharomyces pombe involved in DNA double-strand-break repair. Nucleic Acids Res. 1992; 20(24):6605-11. PMC: 334577. DOI: 10.1093/nar/20.24.6605. View

20.

Sjogren C, Nasmyth K . Sister chromatid cohesion is required for postreplicative double-strand break repair in Saccharomyces cerevisiae. Curr Biol. 2001; 11(12):991-5. DOI: 10.1016/s0960-9822(01)00271-8. View