Effect of Nuclear Architecture on the Efficiency of Double-strand Break Repair

Overview

Journal Nat Cell Biol

Specialty Cell Biology

Date 2013 May 7

PMID 23644470

Citations 77

Authors

Neta Agmon

Batia Liefshitz

Christophe Zimmer

Emmanuelle Fabre

Martin Kupiec

Affiliations

Soon will be listed here.

Abstract

The most dangerous insults to the genome's integrity are those that break both strands of the DNA. Double-strand breaks can be repaired by homologous recombination; in this conserved mechanism, a global genomic homology search finds sequences similar to those near the break, and uses them as a template for DNA synthesis and ligation. Chromosomes occupy restricted territories within the nucleus. We show that yeast genomic regions whose nuclear territories overlap recombine more efficiently than sequences located in spatially distant territories. Tethering of telomeres and centromeres reduces the efficiency of recombination between distant genomic loci, lowering the chances of non-allelic recombination. Our results challenge present models that posit an active scanning of the whole nuclear volume by the broken chromosomal end; they demonstrate that the search for homology is a limiting step in homologous recombination, and emphasize the importance of nuclear organization in genome maintenance.

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References

Agmon N, Pur S, Liefshitz B, Kupiec M . Analysis of repair mechanism choice during homologous recombination. Nucleic Acids Res. 2009; 37(15):5081-92. PMC: 2731894. DOI: 10.1093/nar/gkp495. View

Gauss R, Trautwein M, Sommer T, Spang A . New modules for the repeated internal and N-terminal epitope tagging of genes in Saccharomyces cerevisiae. Yeast. 2004; 22(1):1-12. DOI: 10.1002/yea.1187. View

Schober H, Kalck V, Vega-Palas M, Van Houwe G, Sage D, Unser M . Controlled exchange of chromosomal arms reveals principles driving telomere interactions in yeast. Genome Res. 2007; 18(2):261-71. PMC: 2203624. DOI: 10.1101/gr.6687808. View

Kleckner N, Zickler D, Jones G, Dekker J, Padmore R, Henle J . A mechanical basis for chromosome function. Proc Natl Acad Sci U S A. 2004; 101(34):12592-7. PMC: 515102. DOI: 10.1073/pnas.0402724101. View

Hiraga S, Botsios S, Donaldson A . Histone H3 lysine 56 acetylation by Rtt109 is crucial for chromosome positioning. J Cell Biol. 2008; 183(4):641-51. PMC: 2582893. DOI: 10.1083/jcb.200806065. View

Inbar O, Kupiec M . Recombination between divergent sequences leads to cell death in a mismatch-repair-independent manner. Curr Genet. 2000; 38(1):23-32. DOI: 10.1007/s002940000124. View

Kalhor R, Tjong H, Jayathilaka N, Alber F, Chen L . Genome architectures revealed by tethered chromosome conformation capture and population-based modeling. Nat Biotechnol. 2011; 30(1):90-8. PMC: 3782096. DOI: 10.1038/nbt.2057. 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

Dion V, Kalck V, Horigome C, Towbin B, Gasser S . Increased mobility of double-strand breaks requires Mec1, Rad9 and the homologous recombination machinery. Nat Cell Biol. 2012; 14(5):502-9. DOI: 10.1038/ncb2465. View

10.

Koszul R, Kim K, Prentiss M, Kleckner N, Kameoka S . Meiotic chromosomes move by linkage to dynamic actin cables with transduction of force through the nuclear envelope. Cell. 2008; 133(7):1188-201. PMC: 2601696. DOI: 10.1016/j.cell.2008.04.050. View

11.

Lieberman-Aiden E, van Berkum N, Williams L, Imakaev M, Ragoczy T, Telling A . Comprehensive mapping of long-range interactions reveals folding principles of the human genome. Science. 2009; 326(5950):289-93. PMC: 2858594. DOI: 10.1126/science.1181369. View

12.

Kaye J, Melo J, Cheung S, Vaze M, Haber J, Toczyski D . DNA breaks promote genomic instability by impeding proper chromosome segregation. Curr Biol. 2004; 14(23):2096-106. DOI: 10.1016/j.cub.2004.10.051. View

13.

Berger A, Cabal G, Fabre E, Duong T, Buc H, Nehrbass U . High-resolution statistical mapping reveals gene territories in live yeast. Nat Methods. 2008; 5(12):1031-7. DOI: 10.1038/nmeth.1266. View

14.

Fudenberg G, Getz G, Meyerson M, Mirny L . High order chromatin architecture shapes the landscape of chromosomal alterations in cancer. Nat Biotechnol. 2011; 29(12):1109-13. PMC: 3268007. DOI: 10.1038/nbt.2049. View

15.

Mine-Hattab J, Rothstein R . Increased chromosome mobility facilitates homology search during recombination. Nat Cell Biol. 2012; 14(5):510-7. DOI: 10.1038/ncb2472. View

16.

Aylon Y, Liefshitz B, Bitan-Banin G, Kupiec M . Molecular dissection of mitotic recombination in the yeast Saccharomyces cerevisiae. Mol Cell Biol. 2003; 23(4):1403-17. PMC: 141147. DOI: 10.1128/MCB.23.4.1403-1417.2003. View

17.

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

18.

Guelen L, Pagie L, Brasset E, Meuleman W, Faza M, Talhout W . Domain organization of human chromosomes revealed by mapping of nuclear lamina interactions. Nature. 2008; 453(7197):948-51. DOI: 10.1038/nature06947. View

19.

Soutoglou E, Dorn J, Sengupta K, Jasin M, Nussenzweig A, Ried T . Positional stability of single double-strand breaks in mammalian cells. Nat Cell Biol. 2007; 9(6):675-82. PMC: 2442898. DOI: 10.1038/ncb1591. View

20.

Melamed C, Kupiec M . Effect of donor copy number on the rate of gene conversion in the yeast Saccharomyces cerevisiae. Mol Gen Genet. 1992; 235(1):97-103. DOI: 10.1007/BF00286186. View