A Mec1- and PP4-Dependent checkpoint couples centromere pairing to meiotic recombination

Jill E. Falk; Andrew Chi ho Chan; Eva Hoffmann; Andreas Hochwagen

doi:10.1016/j.devcel.2010.09.006

A Mec1- and PP4-Dependent checkpoint couples centromere pairing to meiotic recombination

Jill E. Falk, Andrew Chi ho Chan, Eva Hoffmann, Andreas Hochwagen

Biology and Genomics

Research output: Contribution to journal › Article › peer-review

Abstract

The faithful alignment of homologous chromosomes during meiotic prophase requires the coordination of DNA double-strand break (DSB) repair with large-scale chromosome reorganization. Here we identify the phosphatase PP4 (Pph3/Psy2) as a mediator of this process in Saccharomyces cerevisiae. In pp4 mutants, early stages of crossover repair and homology-independent pairing of centromeres are coordinately blocked. We traced the loss of centromere pairing to the persistent phosphorylation of the chromosomal protein Zip1 on serine 75. Zip1-S75 is a consensus site for the ATR-like checkpoint kinase Mec1, and centromere pairing is restored in mec1 mutants. Importantly, Zip1-S75 phosphorylation does not alter chromosome synapsis or DSB repair, indicating that Mec1 separates centromere pairing from the other functions of Zip1. The centromeric localization and persistent activity of PP4 during meiotic prophase suggest a model whereby Zip1-S75 phosphorylation dynamically destabilizes homology-independent centromere pairing in response to recombination initiation, thereby coupling meiotic chromosome dynamics to DSB repair.

Original language	English (US)
Pages (from-to)	599-611
Number of pages	13
Journal	Developmental Cell
Volume	19
Issue number	4
DOIs	https://doi.org/10.1016/j.devcel.2010.09.006
State	Published - Oct 19 2010

ASJC Scopus subject areas

Molecular Biology
General Biochemistry, Genetics and Molecular Biology
Developmental Biology
Cell Biology

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10.1016/j.devcel.2010.09.006

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title = "A Mec1- and PP4-Dependent checkpoint couples centromere pairing to meiotic recombination",

abstract = "The faithful alignment of homologous chromosomes during meiotic prophase requires the coordination of DNA double-strand break (DSB) repair with large-scale chromosome reorganization. Here we identify the phosphatase PP4 (Pph3/Psy2) as a mediator of this process in Saccharomyces cerevisiae. In pp4 mutants, early stages of crossover repair and homology-independent pairing of centromeres are coordinately blocked. We traced the loss of centromere pairing to the persistent phosphorylation of the chromosomal protein Zip1 on serine 75. Zip1-S75 is a consensus site for the ATR-like checkpoint kinase Mec1, and centromere pairing is restored in mec1 mutants. Importantly, Zip1-S75 phosphorylation does not alter chromosome synapsis or DSB repair, indicating that Mec1 separates centromere pairing from the other functions of Zip1. The centromeric localization and persistent activity of PP4 during meiotic prophase suggest a model whereby Zip1-S75 phosphorylation dynamically destabilizes homology-independent centromere pairing in response to recombination initiation, thereby coupling meiotic chromosome dynamics to DSB repair.",

author = "Falk, {Jill E.} and Chan, {Andrew Chi ho} and Eva Hoffmann and Andreas Hochwagen",

note = "Funding Information: We are grateful to N. Hunter, S. Roeder, N. Hollingsworth, F. Klein, S. Brill, and A. Desai for sharing strains and reagents for this project and to D. Durocher and F. Klein for sharing unpublished results. We thank G. Bell for help with statistical analyses and B. Joughin, A. Amon, I. Cheeseman, T. Orr-Weaver, and members of the Hochwagen lab for helpful discussions and critical reading of the manuscript. This work was supported in part by research grant 5-FY10-149 from the March of Dimes Foundation and grants from The Stewart Trust and The Smith Family Foundation to A.H. ",

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N1 - Funding Information: We are grateful to N. Hunter, S. Roeder, N. Hollingsworth, F. Klein, S. Brill, and A. Desai for sharing strains and reagents for this project and to D. Durocher and F. Klein for sharing unpublished results. We thank G. Bell for help with statistical analyses and B. Joughin, A. Amon, I. Cheeseman, T. Orr-Weaver, and members of the Hochwagen lab for helpful discussions and critical reading of the manuscript. This work was supported in part by research grant 5-FY10-149 from the March of Dimes Foundation and grants from The Stewart Trust and The Smith Family Foundation to A.H.

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N2 - The faithful alignment of homologous chromosomes during meiotic prophase requires the coordination of DNA double-strand break (DSB) repair with large-scale chromosome reorganization. Here we identify the phosphatase PP4 (Pph3/Psy2) as a mediator of this process in Saccharomyces cerevisiae. In pp4 mutants, early stages of crossover repair and homology-independent pairing of centromeres are coordinately blocked. We traced the loss of centromere pairing to the persistent phosphorylation of the chromosomal protein Zip1 on serine 75. Zip1-S75 is a consensus site for the ATR-like checkpoint kinase Mec1, and centromere pairing is restored in mec1 mutants. Importantly, Zip1-S75 phosphorylation does not alter chromosome synapsis or DSB repair, indicating that Mec1 separates centromere pairing from the other functions of Zip1. The centromeric localization and persistent activity of PP4 during meiotic prophase suggest a model whereby Zip1-S75 phosphorylation dynamically destabilizes homology-independent centromere pairing in response to recombination initiation, thereby coupling meiotic chromosome dynamics to DSB repair.

AB - The faithful alignment of homologous chromosomes during meiotic prophase requires the coordination of DNA double-strand break (DSB) repair with large-scale chromosome reorganization. Here we identify the phosphatase PP4 (Pph3/Psy2) as a mediator of this process in Saccharomyces cerevisiae. In pp4 mutants, early stages of crossover repair and homology-independent pairing of centromeres are coordinately blocked. We traced the loss of centromere pairing to the persistent phosphorylation of the chromosomal protein Zip1 on serine 75. Zip1-S75 is a consensus site for the ATR-like checkpoint kinase Mec1, and centromere pairing is restored in mec1 mutants. Importantly, Zip1-S75 phosphorylation does not alter chromosome synapsis or DSB repair, indicating that Mec1 separates centromere pairing from the other functions of Zip1. The centromeric localization and persistent activity of PP4 during meiotic prophase suggest a model whereby Zip1-S75 phosphorylation dynamically destabilizes homology-independent centromere pairing in response to recombination initiation, thereby coupling meiotic chromosome dynamics to DSB repair.

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A Mec1- and PP4-Dependent checkpoint couples centromere pairing to meiotic recombination

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