Chromosome-autonomous feedback down-regulates meiotic DNA break competence upon synaptonemal complex formation

Xiaojing Mu; Hajime Murakami; Neeman Mohibullah; Scott Keeny

doi:10.1101/gad.342873.120

Chromosome-autonomous feedback down-regulates meiotic DNA break competence upon synaptonemal complex formation

Xiaojing Mu, Hajime Murakami^* (Corresponding Author), Neeman Mohibullah, Scott Keeny^* (Corresponding Author)

^*Corresponding author for this work

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

Abstract

The number of DNA double-strand breaks (DSBs) initiating meiotic recombination is elevated in Saccharomyces cerevisiae mutants that are globally defective in forming crossovers and synaptonemal complex (SC), a protein scaffold juxtaposing homologous chromosomes. These mutants thus appear to lack a negative feedback loop that inhibits DSB formation when homologs engage one another. This feedback is predicted to be chromosome autonomous, but this has not been tested. Moreover, what chromosomal process is recognized as “homolog engagement” remains unclear. To address these questions, we evaluated effects of homolog engagement defects restricted to small portions of the genome using karyotypically abnormal yeast strains with a homeologous chromosome V pair, monosomic V, or trisomy XV. We found that homolog engagement-defective chromosomes incurred more DSBs, concomitant with prolonged retention of the DSB-promoting protein Rec114, while the rest of the genome remained unaffected. SC-deficient, crossover-proficient mutants ecm11 and gmc2 experienced increased DSB numbers diagnostic of homolog engagement defects. These findings support the hypothesis that SC formation provokes DSB protein dissociation, leading in turn to loss of a DSB competent state. Our findings show that DSB number is regulated in a chromosome-autonomous fashion and provide insight into how homeostatic DSB controls respond to aneuploidy during meiosis.

Original language	English
Pages (from-to)	1605-1618
Number of pages	15
Journal	Genes & Development
Volume	34
Early online date	12 Nov 2020
DOIs	https://doi.org/10.1101/gad.342873.120
Publication status	Published - Nov 2020

Bibliographical note

We are grateful to Michael Lichten and Rodney Rothstein for providing strains and plasmids, Miki Shinohara and Keun Kim for discussions and sharing unpublished data, Dean Dawson and Amy MacQueen for sharing unpublished data, Agnes Viale (Memorial Sloan Kettering Cancer Center [MSKCC] Integrated Genomics Core Laboratory) for sequencing, Nicholas Socci (MSKCC Bioinformatics Core Facility) for mapping sequence reads, Stewart Shuman for gifts of T4 RNA ligase, and members of the S.K. laboratory, especially Shintaro Yamada and Devanshi Jain, for discussion and comments on the manuscript. MSKCC core facilities are supported by Cancer Center Support Grant P30
CA008748. This work was supported by National Institute of General Medical Sciences grant R35 GM118092 to S.K.
Author contributions: X.M. performed experiments. X.M. analyzed Spo11-oligo map data with contributions from H.M. N.M. generated the Spo11-oligo map of the trisomy XV strain. X.M., H.M., and S.K. designed the study and wrote the paper. H.M. and S.K. supervised the research. S.K. secured funding

Keywords

aneuploidy
double-strand breaks
meiosis
recombination
trisomy
synaptonemal complex
Spo11

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title = "Chromosome-autonomous feedback down-regulates meiotic DNA break competence upon synaptonemal complex formation",

abstract = "The number of DNA double-strand breaks (DSBs) initiating meiotic recombination is elevated in Saccharomyces cerevisiae mutants that are globally defective in forming crossovers and synaptonemal complex (SC), a protein scaffold juxtaposing homologous chromosomes. These mutants thus appear to lack a negative feedback loop that inhibits DSB formation when homologs engage one another. This feedback is predicted to be chromosome autonomous, but this has not been tested. Moreover, what chromosomal process is recognized as “homolog engagement” remains unclear. To address these questions, we evaluated effects of homolog engagement defects restricted to small portions of the genome using karyotypically abnormal yeast strains with a homeologous chromosome V pair, monosomic V, or trisomy XV. We found that homolog engagement-defective chromosomes incurred more DSBs, concomitant with prolonged retention of the DSB-promoting protein Rec114, while the rest of the genome remained unaffected. SC-deficient, crossover-proficient mutants ecm11 and gmc2 experienced increased DSB numbers diagnostic of homolog engagement defects. These findings support the hypothesis that SC formation provokes DSB protein dissociation, leading in turn to loss of a DSB competent state. Our findings show that DSB number is regulated in a chromosome-autonomous fashion and provide insight into how homeostatic DSB controls respond to aneuploidy during meiosis. ",

keywords = "aneuploidy, double-strand breaks, meiosis, recombination, trisomy, synaptonemal complex, Spo11",

author = "Xiaojing Mu and Hajime Murakami and Neeman Mohibullah and Scott Keeny",

note = "We are grateful to Michael Lichten and Rodney Rothstein for providing strains and plasmids, Miki Shinohara and Keun Kim for discussions and sharing unpublished data, Dean Dawson and Amy MacQueen for sharing unpublished data, Agnes Viale (Memorial Sloan Kettering Cancer Center [MSKCC] Integrated Genomics Core Laboratory) for sequencing, Nicholas Socci (MSKCC Bioinformatics Core Facility) for mapping sequence reads, Stewart Shuman for gifts of T4 RNA ligase, and members of the S.K. laboratory, especially Shintaro Yamada and Devanshi Jain, for discussion and comments on the manuscript. MSKCC core facilities are supported by Cancer Center Support Grant P30 CA008748. This work was supported by National Institute of General Medical Sciences grant R35 GM118092 to S.K. Author contributions: X.M. performed experiments. X.M. analyzed Spo11-oligo map data with contributions from H.M. N.M. generated the Spo11-oligo map of the trisomy XV strain. X.M., H.M., and S.K. designed the study and wrote the paper. H.M. and S.K. supervised the research. S.K. secured funding",

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doi = "10.1101/gad.342873.120",

language = "English",

volume = "34",

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journal = "Genes & Development",

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T1 - Chromosome-autonomous feedback down-regulates meiotic DNA break competence upon synaptonemal complex formation

AU - Mu, Xiaojing

AU - Murakami, Hajime

AU - Mohibullah, Neeman

AU - Keeny, Scott

N1 - We are grateful to Michael Lichten and Rodney Rothstein for providing strains and plasmids, Miki Shinohara and Keun Kim for discussions and sharing unpublished data, Dean Dawson and Amy MacQueen for sharing unpublished data, Agnes Viale (Memorial Sloan Kettering Cancer Center [MSKCC] Integrated Genomics Core Laboratory) for sequencing, Nicholas Socci (MSKCC Bioinformatics Core Facility) for mapping sequence reads, Stewart Shuman for gifts of T4 RNA ligase, and members of the S.K. laboratory, especially Shintaro Yamada and Devanshi Jain, for discussion and comments on the manuscript. MSKCC core facilities are supported by Cancer Center Support Grant P30 CA008748. This work was supported by National Institute of General Medical Sciences grant R35 GM118092 to S.K. Author contributions: X.M. performed experiments. X.M. analyzed Spo11-oligo map data with contributions from H.M. N.M. generated the Spo11-oligo map of the trisomy XV strain. X.M., H.M., and S.K. designed the study and wrote the paper. H.M. and S.K. supervised the research. S.K. secured funding

PY - 2020/11

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N2 - The number of DNA double-strand breaks (DSBs) initiating meiotic recombination is elevated in Saccharomyces cerevisiae mutants that are globally defective in forming crossovers and synaptonemal complex (SC), a protein scaffold juxtaposing homologous chromosomes. These mutants thus appear to lack a negative feedback loop that inhibits DSB formation when homologs engage one another. This feedback is predicted to be chromosome autonomous, but this has not been tested. Moreover, what chromosomal process is recognized as “homolog engagement” remains unclear. To address these questions, we evaluated effects of homolog engagement defects restricted to small portions of the genome using karyotypically abnormal yeast strains with a homeologous chromosome V pair, monosomic V, or trisomy XV. We found that homolog engagement-defective chromosomes incurred more DSBs, concomitant with prolonged retention of the DSB-promoting protein Rec114, while the rest of the genome remained unaffected. SC-deficient, crossover-proficient mutants ecm11 and gmc2 experienced increased DSB numbers diagnostic of homolog engagement defects. These findings support the hypothesis that SC formation provokes DSB protein dissociation, leading in turn to loss of a DSB competent state. Our findings show that DSB number is regulated in a chromosome-autonomous fashion and provide insight into how homeostatic DSB controls respond to aneuploidy during meiosis.

AB - The number of DNA double-strand breaks (DSBs) initiating meiotic recombination is elevated in Saccharomyces cerevisiae mutants that are globally defective in forming crossovers and synaptonemal complex (SC), a protein scaffold juxtaposing homologous chromosomes. These mutants thus appear to lack a negative feedback loop that inhibits DSB formation when homologs engage one another. This feedback is predicted to be chromosome autonomous, but this has not been tested. Moreover, what chromosomal process is recognized as “homolog engagement” remains unclear. To address these questions, we evaluated effects of homolog engagement defects restricted to small portions of the genome using karyotypically abnormal yeast strains with a homeologous chromosome V pair, monosomic V, or trisomy XV. We found that homolog engagement-defective chromosomes incurred more DSBs, concomitant with prolonged retention of the DSB-promoting protein Rec114, while the rest of the genome remained unaffected. SC-deficient, crossover-proficient mutants ecm11 and gmc2 experienced increased DSB numbers diagnostic of homolog engagement defects. These findings support the hypothesis that SC formation provokes DSB protein dissociation, leading in turn to loss of a DSB competent state. Our findings show that DSB number is regulated in a chromosome-autonomous fashion and provide insight into how homeostatic DSB controls respond to aneuploidy during meiosis.

KW - aneuploidy

KW - double-strand breaks

KW - meiosis

KW - recombination

KW - trisomy

KW - synaptonemal complex

KW - Spo11

UR - http://dx.doi.org/10.1101/gad.342873.120

U2 - 10.1101/gad.342873.120

DO - 10.1101/gad.342873.120

M3 - Article

SN - 0890-9369

VL - 34

SP - 1605

EP - 1618

JO - Genes & Development

JF - Genes & Development

ER -

Chromosome-autonomous feedback down-regulates meiotic DNA break competence upon synaptonemal complex formation

Abstract

Bibliographical note

Keywords

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