Multi-step control of homologous recombination via Mec1/ATR suppresses chromosomal rearrangements.

Autor:	Xie B; Department of Molecular Biology and Genetics, Weill Institute for Cell and Molecular Biology, Cornell University, Ithaca, NY, USA., Sanford EJ; Department of Molecular Biology and Genetics, Weill Institute for Cell and Molecular Biology, Cornell University, Ithaca, NY, USA., Hung SH; Department of Microbiology and Molecular Genetics, University of California, Davis, Davis, CA, USA., Wagner M; Department of Molecular Biology and Genetics, Weill Institute for Cell and Molecular Biology, Cornell University, Ithaca, NY, USA., Heyer WD; Department of Microbiology and Molecular Genetics, University of California, Davis, Davis, CA, USA., Smolka MB; Department of Molecular Biology and Genetics, Weill Institute for Cell and Molecular Biology, Cornell University, Ithaca, NY, USA. mbs266@cornell.edu.
Jazyk:	angličtina
Zdroj:	The EMBO journal [EMBO J] 2024 Jul; Vol. 43 (14), pp. 3027-3043. Date of Electronic Publication: 2024 Jun 05.
DOI:	10.1038/s44318-024-00139-9
Abstrakt:	The Mec1/ATR kinase is crucial for genome stability, yet the mechanism by which it prevents gross chromosomal rearrangements (GCRs) remains unknown. Here we find that in cells with deficient Mec1 signaling, GCRs accumulate due to the deregulation of multiple steps in homologous recombination (HR). Mec1 primarily suppresses GCRs through its role in activating the canonical checkpoint kinase Rad53, which ensures the proper control of DNA end resection. Upon loss of Rad53 signaling and resection control, Mec1 becomes hyperactivated and triggers a salvage pathway in which the Sgs1 helicase is recruited to sites of DNA lesions via the 911-Dpb11 scaffolds and phosphorylated by Mec1 to favor heteroduplex rejection and limit HR-driven GCR accumulation. Fusing an ssDNA recognition domain to Sgs1 bypasses the requirement of Mec1 signaling for GCR suppression and nearly eliminates D-loop formation, thus preventing non-allelic recombination events. We propose that Mec1 regulates multiple steps of HR to prevent GCRs while ensuring balanced HR usage when needed for promoting tolerance to replication stress. (© 2024. The Author(s).)
Databáze:	MEDLINE
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