Cell cycle regulation of DNA double-strand break end resection by Cdk1-dependent Dna2 phosphorylation
Open Access
- 14 August 2011
- journal article
- research article
- Published by Springer Science and Business Media LLC in Nature Structural & Molecular Biology
- Vol. 18 (9), 1015-1019
- https://doi.org/10.1038/nsmb.2105
Abstract
Resection of DNA 5′ ends is the initial step for repair of double-strand breaks via homologous recombination. DNA resection is controlled in a cell-cycle dependent manner, with yeast Cdk1 known to control Sae2, a nuclease that initiates resection. Now recruitment to DNA damage sites of Dna2, a nuclease responsible for extensive resection, is also shown to be controlled by Cdk1. DNA recombination pathways are regulated by the cell cycle to coordinate with replication. Cyclin-dependent kinase (Cdk1) promotes efficient 5′ strand resection at DNA double-strand breaks (DSBs), the initial step of homologous recombination and damage checkpoint activation. The Mre11–Rad50–Xrs2 complex with Sae2 initiates resection, whereas two nucleases, Exo1 and Dna2, and the DNA helicase–topoisomerase complex Sgs1–Top3–Rmi1 generate longer ssDNA at DSBs. Using Saccharomyces cerevisiae, we provide evidence for Cdk1-dependent phosphorylation of the resection nuclease Dna2 at Thr4, Ser17 and Ser237 that stimulates its recruitment to DSBs, resection and subsequent Mec1-dependent phosphorylation. Poorly recruited dna2T4A S17A S237A and dna2ΔN248 mutant proteins promote resection only in the presence of Exo1, suggesting cross-talk between Dna2- and Exo1-dependent resection pathways.Keywords
This publication has 46 references indexed in Scilit:
- Exo1 Competes with Repair Synthesis, Converts NER Intermediates to Long ssDNA Gaps, and Promotes Checkpoint ActivationMolecular Cell, 2010
- Saccharomyces cerevisiae Mre11/Rad50/Xrs2 and Ku proteins regulate association of Exo1 and Dna2 with DNA breaksThe EMBO Journal, 2010
- Mechanism of the ATP-dependent DNA end-resection machinery from Saccharomyces cerevisiaeNature, 2010
- Cdk1 Targets Srs2 to Complete Synthesis-Dependent Strand Annealing and to Promote Recombinational RepairPLoS Genetics, 2010
- An overview of Cdk1-controlled targets and processesCell Division, 2010
- CtIP-BRCA1 modulates the choice of DNA double-strand-break repair pathway throughout the cell cycleNature, 2009
- DNA end resection, homologous recombination and DNA damage checkpoint activation require CDK1Nature, 2004
- Two modes of DNA double-strand break repair are reciprocally regulated through the fission yeast cell cycleJournal of Bone and Joint Surgery, 2004
- In Vivo Roles of Rad52, Rad54, and Rad55 Proteins in Rad51-Mediated RecombinationMolecular Cell, 2003
- Genomic sequencing.Proceedings of the National Academy of Sciences of the United States of America, 1984