Positive regulation of meiotic DNA double-strand break formation by activation of the DNA damage checkpoint kinase Mec1(ATR)

Gray, Stephen; Allison, Rachal M.; Garcia, Valerie; Goldman, Alastair S. H.; Neale, Matthew J.

Abstract

During meiosis, formation and repair of programmed DNA double-strand breaks (DSBs) create genetic exchange between homologous chromosomes-a process that is critical for reductional meiotic chromosome segregation andthe production of genetically diverse sexually reproducing populations. Meiotic DSB formation is a complex process, requiring numerous proteins, of which Spo11 is the evolutionarily conserved catalytic subunit. Precisely how Spo11 and its accessory proteins function or are regulated is unclear. Here, we use Saccharomyces cerevisiae to reveal that meiotic DSB formation is modulated by the Mec1(ATR) branch of the DNA damage signalling cascade, promoting DSB formation when Spo11-mediated catalysis is compromised. Activation of the positive feedback pathway correlates with the formation of single-strandedDNA (ssDNA) recombination intermediates and activation of the downstream kinase, Mek1. We show that the requirement for checkpoint activation can be rescued by prolonging meiotic prophase by deleting the NDT80 transcription factor, and that even transient prophase arrest caused by Ndt80 depletion is sufficient to restore meiotic spore viability in checkpoint mutants. Our observations are unexpected given recent reports that the complementary kinase pathway Tel1(ATM) acts to inhibit DSB formation. We propose that such antagonistic regulation of DSB formation by Mec1 and Tel1 creates a regulatory mechanism, where the absolute frequency of DSBs is maintained at a level optimal for genetic exchange and efficient chromosome segregation. © 2013 The Authors.

Citation

Gray, S., Allison, R. M., Garcia, V., Goldman, A. S. H., & Neale, M. J. (2013). Positive regulation of meiotic DNA double-strand break formation by activation of the DNA damage checkpoint kinase Mec1(ATR). Open Biology, 3(7), 130019. https://doi.org/10.1098/rsob.130019

• Journal Article Type: Article
• Acceptance Date: Jul 5, 2013
• Online Publication Date: Jul 1, 2013
• Publication Date: Jul 1, 2013
• Deposit Date: Nov 11, 2019
• Journal: Open Biology
• Electronic ISSN: 2046-2441
• Publisher: The Royal Society
• Peer Reviewed: Peer Reviewed
• Volume: 3
• Issue: 7
• Pages: 130019
• DOI: https://doi.org/10.1098/rsob.130019
• Public URL: https://nottingham-repository.worktribe.com/output/3198638
• Additional Information: Received: 2013-02-01; Accepted: 2013-07-05; Published: 2013-07-01