Regulatory control of DNA end resection by Sae2 phosphorylation

Cannavo, Elda, Johnson, Dominic, Andres, Sara, Kissling, Vera, Reinert, Julia, Garcia, Valerie, Erie, Dorothy, Hess, Daniel, Thomä, Nicolas, Enchev, Radoslav, Peter, Matthias, Williams, Scott, Neale, Matt and Cejka, Petr (2018) Regulatory control of DNA end resection by Sae2 phosphorylation. Nature Communications, 9. p. 4016. ISSN 2041-1723

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DNA end resection plays a critical function in DNA double-strand break repair pathway choice. Resected DNA ends are refractory to end-joining mechanisms and are instead channeled to homology-directed repair. Using biochemical, genetic, and imaging methods, we show that phosphorylation of Saccharomyces cerevisiae Sae2 controls its capacity to promote the Mre11-Rad50-Xrs2 (MRX) nuclease to initiate resection of blocked DNA ends by at least two distinct mechanisms. First, DNA damage and cell cycle-dependent phosphorylation leads to Sae2 tetramerization. Second, and independently, phosphorylation of the conserved C-terminal domain of Sae2 is a prerequisite for its physical interaction with Rad50, which is also crucial to promote the MRX endonuclease. The lack of this interaction explains the phenotype of rad50S mutants defective in the processing of Spo11-bound DNA ends during meiotic recombination. Our results define how phosphorylation controls the initiation of DNA end resection and therefore the choice between the key DNA double-strand break repair mechanisms.

Item Type: Article
Schools and Departments: School of Life Sciences > Sussex Centre for Genome Damage and Stability
Research Centres and Groups: Genome Damage and Stability Centre
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Depositing User: Matt Neale
Date Deposited: 17 May 2019 10:19
Last Modified: 01 Jul 2019 15:01

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Project NameSussex Project NumberFunderFunder Ref
Biochemical reconstitution of DNA repair reactions on intact chromatinG0986EUROPEAN UNION311336
Control and impact of meiotic DNA resection on recombination and genome stabilityG1538BBSRC-BIOTECHNOLOGY & BIOLOGICAL SCIENCES RESEARCH COUNCILBB/M010279/1
Repair of covalent protein-linked DNA double-strand breaks (ext to R33Y - but separate grant)G0866ROYAL SOCIETYUF110009
Spatial regulation of meiotic recombinationUnsetWELLCOME TRUST200843/Z/16/Z