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Mol Cell. 2015 Mar 5;57(5):797-811. doi: 10.1016/j.molcel.2014.12.027. Epub 2015 Feb 5.

Gradual implementation of the meiotic recombination program via checkpoint pathways controlled by global DSB levels.

Author information

1
Center for Gene Regulation in Health and Disease and Department of Biological Sciences, Cleveland State University, Cleveland, OH 44115, USA.
2
Department of Molecular Genetics and Cell Biology, University of Chicago, Cummings Life Science Center, Chicago, IL 60637, USA; Department of Radiation and Cellular Oncology, University of Chicago, Chicago, IL 60637, USA.
3
Department of Molecular Genetics and Cell Biology, University of Chicago, Cummings Life Science Center, Chicago, IL 60637, USA; Department of Radiation and Cellular Oncology, University of Chicago, Chicago, IL 60637, USA; Committee on Genetics, University of Chicago, Chicago, IL 60637, USA.
4
Center for Gene Regulation in Health and Disease and Department of Biological Sciences, Cleveland State University, Cleveland, OH 44115, USA; Department of Cellular and Molecular Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA; Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, OH 44106, USA. Electronic address: g.boerner@csuohio.edu.

Abstract

During meiosis, Spo11-induced double-strand breaks (DSBs) are processed into crossovers, ensuring segregation of homologous chromosomes (homologs). Meiotic DSB processing entails 5' end resection and preferred strand exchange with the homolog rather than the sister chromatid (homolog bias). In many organisms, DSBs appear gradually along the genome. Here we report unexpected effects of global DSB levels on local recombination events. Early-occurring, low-abundance "scout" DSBs lack homolog bias. Their resection and interhomolog processing are controlled by the conserved checkpoint proteins Tel1(ATM) kinase and Pch2(TRIP13) ATPase. Processing pathways controlled by Mec1(ATR) kinase take over these functions only above a distinct DSB threshold, resulting in progressive strengthening of the homolog bias. We conclude that Tel1(ATM)/Pch2 and Mec1(ATR) DNA damage response pathways are sequentially activated during wild-type meiosis because of their distinct sensitivities to global DSB levels. Moreover, relative DSB order controls the DSB repair pathway choice and, ultimately, recombination outcome.

PMID:
25661491
PMCID:
PMC4392720
DOI:
10.1016/j.molcel.2014.12.027
[Indexed for MEDLINE]
Free PMC Article

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