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 ligation1. Chromosomes occupy restricted territories within the nucleus2,3. We show that yeast genomic regions whose nuclear territories overlap recombine more efficiently than sequences located in spatially distant territories. Tethering of telomeres and centromeres4,5 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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Acknowledgements
This work was supported by grants from the Israel Science Foundation and the Israeli Ministry of Science and Technology to M.K. N.A. was supported by an Eshkol fellowship from the Israeli Ministry of Science and Technology. C.Z. thanks Institut Pasteur, Agence Nationale de la Recherche (grant ANR-09-PIRI-0024) and Fondation pour la Recherche Médicale (Équipe FRM) for support. E.F. thanks Institut Pasteur and Agence Nationale de la Recherche (grant ANR-09-PIRI-0024).
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E.F., C.Z., N.A. and M.K. conceived the project and wrote the paper. N.A., B.L. and M.K. created yeast strains and carried out the recombination experiments. E.F. mapped the cassette locations within the nucleus and C.Z. carried out the statistical analyses.
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Agmon, N., Liefshitz, B., Zimmer, C. et al. Effect of nuclear architecture on the efficiency of double-strand break repair. Nat Cell Biol 15, 694–699 (2013). https://doi.org/10.1038/ncb2745
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DOI: https://doi.org/10.1038/ncb2745
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