DNA double-strand break repair is critical for cell viability and involves highly coordinated pathways to restore DNA integrity at the lesion. An early event during homology-dependent repair is resection of the break to generate progressively longer 3′ single-strand tails that are used to identify suitable templates for repair1. Sister chromatids provide near-perfect sequence homology and are therefore the preferred templates during homologous recombination2,3. To provide a bias for the use of sisters as donors, cohesin—the complex that tethers sister chromatids together4—is recruited to the break5,6 to enforce physical proximity. Here we show that DNA breaks promote dissociation of cohesin loaded during the previous S phase in budding yeast, and that damage-induced dissociation of cohesin requires separase, the protease that dissolves cohesion in anaphase7. Moreover, a separase-resistant allele of the gene coding for the α-kleisin subunit of cohesin, Mcd1 (also known as Scc1), reduces double-strand break resection and compromises the efficiency of repair even when loaded during DNA damage. We conclude that post-replicative DNA repair involves cohesin dissociation by separase to promote accessibility to repair factors during the coordinated cellular response to restore DNA integrity.
Subscribe to Journal
Get full journal access for 1 year
only $3.90 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Pâques, F. & Haber, J. E. Multiple pathways of recombination induced by double-strand breaks in Saccharomyces cerevisiae. Microbiol. Mol. Biol. Rev. 63, 349–404 (1999)
Kadyk, L. C. & Hartwell, L. H. Sister chromatids are preferred over homologs as substrates for recombinational repair in Saccharomyces cerevisiae. Genetics 132, 387–402 (1992)
Johnson, R. D. & Jasin, M. Sister chromatid gene conversion is a prominent double-strand break repair pathway in mammalian cells. EMBO J. 19, 3398–3407 (2000)
Nasmyth, K. Cohesin: a catenase with separate entry and exit gates? Nature Cell Biol. 13, 1170–1177 (2011)
Unal, E. et al. DNA damage response pathway uses histone modification to assemble a double-strand break-specific cohesin domain. Mol. Cell 16, 991–1002 (2004)
Strom, L., Lindroos, H. B., Shirahige, K. & Sjogren, C. Postreplicative recruitment of cohesin to double-strand breaks is required for DNA repair. Mol. Cell 16, 1003–1015 (2004)
Uhlmann, F., Lottspeich, F. & Nasmyth, K. Sister-chromatid separation at anaphase onset is promoted by cleavage of the cohesin subunit Scc1. Nature 400, 37–42 (1999)
Strom, L. et al. Postreplicative formation of cohesion is required for repair and induced by a single DNA break. Science 317, 242–245 (2007)
Unal, E., Heidinger-Pauli, J. M. & Koshland, D. DNA double-strand breaks trigger genome-wide sister-chromatid cohesion through Eco1 (Ctf7). Science 317, 245–248 (2007)
Heidinger-Pauli, J. M., Mert, O., Davenport, C., Guacci, V. & Koshland, D. Systematic reduction of cohesin differentially affects chromosome segregation, condensation, and DNA repair. Curr. Biol. 20, 957–963 (2010)
Heidinger-Pauli, J. M., Unal, E. & Koshland, D. Distinct targets of the Eco1 acetyltransferase modulate cohesion in S phase and in response to DNA damage. Mol. Cell 34, 311–321 (2009)
Nagao, K., Adachi, Y. & Yanagida, M. Separase-mediated cleavage of cohesin at interphase is required for DNA repair. Nature 430, 1044–1048 (2004)
Baskerville, C., Segal, M. & Reed, S. I. The protease activity of yeast separase (esp1) is required for anaphase spindle elongation independently of its role in cleavage of cohesin. Genetics 178, 2361–2372 (2008)
Heidinger-Pauli, J. M., Unal, E., Guacci, V. & Koshland, D. The kleisin subunit of cohesin dictates damage-induced cohesion. Mol. Cell 31, 47–56 (2008)
Zhu, Z., Chung, W. H., Shim, E. Y., Lee, S. E. & Ira, G. Sgs1 helicase and two nucleases Dna2 and Exo1 resect DNA double-strand break ends. Cell 134, 981–994 (2008)
Mimitou, E. P. & Symington, L. S. Sae2, Exo1 and Sgs1 collaborate in DNA double-strand break processing. Nature 455, 770–774 (2008)
Shim, E. Y. et al. Saccharomyces cerevisiae Mre11/Rad50/Xrs2 and Ku proteins regulate association of Exo1 and Dna2 with DNA breaks. EMBO J. 29, 3370–3380 (2010)
Vaze, M. B. et al. Recovery from checkpoint-mediated arrest after repair of a double-strand break requires Srs2 helicase. Mol. Cell 10, 373–385 (2002)
Jain, S. et al. A recombination execution checkpoint regulates the choice of homologous recombination pathway during DNA double-strand break repair. Genes Dev. 23, 291–303 (2009)
We would like to thank D. Koshland, E. Unal, J. Haber, G. Ira and K. Nasmyth for providing valuable strains. We thank members of the Aragon laboratory, P. Ullal, S. Farmer, K. Pegram, J. Torres-Rosell and M. Merkenschlager for discussions and reading of the manuscript. This work was funded by the Intramural Research Program of the Medical Research Council UK.
The authors declare no competing financial interests.
About this article
Cite this article
McAleenan, A., Clemente-Blanco, A., Cordon-Preciado, V. et al. Post-replicative repair involves separase-dependent removal of the kleisin subunit of cohesin. Nature 493, 250–254 (2013). https://doi.org/10.1038/nature11630
Separase activity distribution can be a marker of major molecular response and proliferation of CD34+ cells in TKI-treated chronic myeloid leukemia patients
Annals of Hematology (2020)
Biochemical Pharmacology (2020)
A genetic interaction map centered on cohesin reveals auxiliary factors involved in sister chromatid cohesion in S. cerevisiae
Journal of Cell Science (2020)
Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis (2020)
Pathology - Research and Practice (2020)