1. Multi-step control of homologous recombination via Mec1/ATR suppresses chromosomal rearrangements
- Author
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Xie, Bokun, Sanford, Ethan James, Hung, Shih-Hsun, Wagner, Mateusz, Heyer, Wolf-Dietrich, and Smolka, Marcus B
- Subjects
Biochemistry and Cell Biology ,Biological Sciences ,Genetics ,Prevention ,Human Genome ,Saccharomyces cerevisiae Proteins ,Saccharomyces cerevisiae ,Protein Serine-Threonine Kinases ,Homologous Recombination ,Intracellular Signaling Peptides and Proteins ,Cell Cycle Proteins ,Checkpoint Kinase 2 ,RecQ Helicases ,Signal Transduction ,Phosphorylation ,Chromosome Aberrations ,Gene Rearrangement ,Mec1 ,Sgs1 ,Resection ,Chromosomal Rearrangement ,Information and Computing Sciences ,Medical and Health Sciences ,Developmental Biology ,Biological sciences ,Biomedical and clinical sciences - Abstract
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.
- Published
- 2024