Multilayered mechanisms ensure that short chromosomes recombine in meiosis

Hajime Murakami; Isabel Lam; Pei-Ching Huang; Jacquelyn Song; Megan van Overbeek; Scott Keeny

doi:10.1038/s41586-020-2248-2

Multilayered mechanisms ensure that short chromosomes recombine in meiosis

Hajime Murakami, Isabel Lam, Pei-Ching Huang, Jacquelyn Song, Megan van Overbeek, Scott Keeny

Medical Sciences

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

Abstract

In most species, homologous chromosomes must recombine in order to segregate accurately during meiosis1. Because small chromosomes would be at risk of missegregation if recombination were randomly distributed, the double-strand breaks (DSBs) that initiate recombination are not located arbitrarily2. How the nonrandomness of DSB distributions is controlled is not understood, although several pathways are known to regulate the timing, location and number of DSBs. Meiotic DSBs are generated by Spo11 and accessory DSB proteins, including Rec114 and Mer2, which assemble on chromosomes3,4,5,6,7 and are nearly universal in eukaryotes8,9,10,11. Here we demonstrate how Saccharomyces cerevisiae integrates multiple temporally distinct pathways to regulate the binding of Rec114 and Mer2 to chromosomes, thereby controlling the duration of a DSB-competent state. The engagement of homologous chromosomes with each other regulates the dissociation of Rec114 and Mer2 later in prophase I, whereas the timing of replication and the proximity to centromeres or telomeres influence the accumulation of Rec114 and Mer2 early in prophase I. Another early mechanism enhances the binding of Rec114 and Mer2 specifically on the shortest chromosomes, and is subject to selection pressure to maintain the hyperrecombinogenic properties of these chromosomes. Thus, the karyotype of an organism and its risk of meiotic missegregation influence the shape and evolution of its recombination landscape. Our results provide a cohesive view of a multifaceted and evolutionarily constrained system that allocates DSBs to all pairs of homologous chromosomes.

Original language	English
Pages (from-to)	124-128
Journal	Nature
Volume	582
Early online date	6 May 2020
DOIs	https://doi.org/10.1038/s41586-020-2248-2
Publication status	Published - 4 Jun 2020

Bibliographical note

Acknowledgements
We thank A. Viale and N. Mohibullah of the Memorial Sloan Kettering Cancer Center (MSKCC) Integrated Genomics Operation for DNA sequencing; N. Socci at the MSKCC Bioinformatics Core Facility for mapping ChIP–seq and Spo11-oligo reads; and members of the Keeney laboratory, especially S. Yamada for advice on data analysis and L. Acquaviva for sharing unpublished information. We thank V. Subramanian, A. Hochwagen and F. Klein for discussions and for sharing unpublished information; and M. Lichten, E. Louis, K. Ohta, A. Amon, W. Zachariae, J. Matos and R. Rothstein for strains or plasmids. I.L. and M.v.O. were supported in part by National Institutes of Health (NIH) fellowships F31 GM097861 and F32 GM096692, respectively. This work was supported by NIH grants R01 GM058673 and R35 GM118092 to S.K. MSKCC core facilities are supported by NCI Cancer Center Support Grant P30 CA008748.

Data Availability Statement

Data availability
All sequencing data have been deposited in the Gene Expression Omnibus (GEO) with the accession numbers GSE52970 (Rec114 ChIP–seq, including tof1), GSE84859 (Spo11 oligonucleotides in hop1 and red1), GSE119786 (Mer2 ChIP–seq), GSE119787 (all Rec114 ChIP–seq data generated in this study) and GSE119689 (Spo11-oligonucleotide maps in the wild type at 4 h and 6 h).

Code availability
Custom code for Spo11-oligonucleotide mapping has been previously published and is available online (see Methods for references).

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10.1038/s41586-020-2248-2

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abstract = "In most species, homologous chromosomes must recombine in order to segregate accurately during meiosis1. Because small chromosomes would be at risk of missegregation if recombination were randomly distributed, the double-strand breaks (DSBs) that initiate recombination are not located arbitrarily2. How the nonrandomness of DSB distributions is controlled is not understood, although several pathways are known to regulate the timing, location and number of DSBs. Meiotic DSBs are generated by Spo11 and accessory DSB proteins, including Rec114 and Mer2, which assemble on chromosomes3,4,5,6,7 and are nearly universal in eukaryotes8,9,10,11. Here we demonstrate how Saccharomyces cerevisiae integrates multiple temporally distinct pathways to regulate the binding of Rec114 and Mer2 to chromosomes, thereby controlling the duration of a DSB-competent state. The engagement of homologous chromosomes with each other regulates the dissociation of Rec114 and Mer2 later in prophase I, whereas the timing of replication and the proximity to centromeres or telomeres influence the accumulation of Rec114 and Mer2 early in prophase I. Another early mechanism enhances the binding of Rec114 and Mer2 specifically on the shortest chromosomes, and is subject to selection pressure to maintain the hyperrecombinogenic properties of these chromosomes. Thus, the karyotype of an organism and its risk of meiotic missegregation influence the shape and evolution of its recombination landscape. Our results provide a cohesive view of a multifaceted and evolutionarily constrained system that allocates DSBs to all pairs of homologous chromosomes.",

author = "Hajime Murakami and Isabel Lam and Pei-Ching Huang and Jacquelyn Song and {van Overbeek}, Megan and Scott Keeny",

note = "Acknowledgements We thank A. Viale and N. Mohibullah of the Memorial Sloan Kettering Cancer Center (MSKCC) Integrated Genomics Operation for DNA sequencing; N. Socci at the MSKCC Bioinformatics Core Facility for mapping ChIP–seq and Spo11-oligo reads; and members of the Keeney laboratory, especially S. Yamada for advice on data analysis and L. Acquaviva for sharing unpublished information. We thank V. Subramanian, A. Hochwagen and F. Klein for discussions and for sharing unpublished information; and M. Lichten, E. Louis, K. Ohta, A. Amon, W. Zachariae, J. Matos and R. Rothstein for strains or plasmids. I.L. and M.v.O. were supported in part by National Institutes of Health (NIH) fellowships F31 GM097861 and F32 GM096692, respectively. This work was supported by NIH grants R01 GM058673 and R35 GM118092 to S.K. MSKCC core facilities are supported by NCI Cancer Center Support Grant P30 CA008748.",

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doi = "10.1038/s41586-020-2248-2",

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AU - Murakami, Hajime

AU - Lam, Isabel

AU - Huang, Pei-Ching

AU - Song, Jacquelyn

AU - van Overbeek, Megan

AU - Keeny, Scott

N1 - Acknowledgements We thank A. Viale and N. Mohibullah of the Memorial Sloan Kettering Cancer Center (MSKCC) Integrated Genomics Operation for DNA sequencing; N. Socci at the MSKCC Bioinformatics Core Facility for mapping ChIP–seq and Spo11-oligo reads; and members of the Keeney laboratory, especially S. Yamada for advice on data analysis and L. Acquaviva for sharing unpublished information. We thank V. Subramanian, A. Hochwagen and F. Klein for discussions and for sharing unpublished information; and M. Lichten, E. Louis, K. Ohta, A. Amon, W. Zachariae, J. Matos and R. Rothstein for strains or plasmids. I.L. and M.v.O. were supported in part by National Institutes of Health (NIH) fellowships F31 GM097861 and F32 GM096692, respectively. This work was supported by NIH grants R01 GM058673 and R35 GM118092 to S.K. MSKCC core facilities are supported by NCI Cancer Center Support Grant P30 CA008748.

PY - 2020/6/4

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N2 - In most species, homologous chromosomes must recombine in order to segregate accurately during meiosis1. Because small chromosomes would be at risk of missegregation if recombination were randomly distributed, the double-strand breaks (DSBs) that initiate recombination are not located arbitrarily2. How the nonrandomness of DSB distributions is controlled is not understood, although several pathways are known to regulate the timing, location and number of DSBs. Meiotic DSBs are generated by Spo11 and accessory DSB proteins, including Rec114 and Mer2, which assemble on chromosomes3,4,5,6,7 and are nearly universal in eukaryotes8,9,10,11. Here we demonstrate how Saccharomyces cerevisiae integrates multiple temporally distinct pathways to regulate the binding of Rec114 and Mer2 to chromosomes, thereby controlling the duration of a DSB-competent state. The engagement of homologous chromosomes with each other regulates the dissociation of Rec114 and Mer2 later in prophase I, whereas the timing of replication and the proximity to centromeres or telomeres influence the accumulation of Rec114 and Mer2 early in prophase I. Another early mechanism enhances the binding of Rec114 and Mer2 specifically on the shortest chromosomes, and is subject to selection pressure to maintain the hyperrecombinogenic properties of these chromosomes. Thus, the karyotype of an organism and its risk of meiotic missegregation influence the shape and evolution of its recombination landscape. Our results provide a cohesive view of a multifaceted and evolutionarily constrained system that allocates DSBs to all pairs of homologous chromosomes.

AB - In most species, homologous chromosomes must recombine in order to segregate accurately during meiosis1. Because small chromosomes would be at risk of missegregation if recombination were randomly distributed, the double-strand breaks (DSBs) that initiate recombination are not located arbitrarily2. How the nonrandomness of DSB distributions is controlled is not understood, although several pathways are known to regulate the timing, location and number of DSBs. Meiotic DSBs are generated by Spo11 and accessory DSB proteins, including Rec114 and Mer2, which assemble on chromosomes3,4,5,6,7 and are nearly universal in eukaryotes8,9,10,11. Here we demonstrate how Saccharomyces cerevisiae integrates multiple temporally distinct pathways to regulate the binding of Rec114 and Mer2 to chromosomes, thereby controlling the duration of a DSB-competent state. The engagement of homologous chromosomes with each other regulates the dissociation of Rec114 and Mer2 later in prophase I, whereas the timing of replication and the proximity to centromeres or telomeres influence the accumulation of Rec114 and Mer2 early in prophase I. Another early mechanism enhances the binding of Rec114 and Mer2 specifically on the shortest chromosomes, and is subject to selection pressure to maintain the hyperrecombinogenic properties of these chromosomes. Thus, the karyotype of an organism and its risk of meiotic missegregation influence the shape and evolution of its recombination landscape. Our results provide a cohesive view of a multifaceted and evolutionarily constrained system that allocates DSBs to all pairs of homologous chromosomes.

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DO - 10.1038/s41586-020-2248-2

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JO - Nature

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ER -

Multilayered mechanisms ensure that short chromosomes recombine in meiosis

Abstract

Bibliographical note

Data Availability Statement

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