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Cell. 2016 Oct 20;167(3):695-708.e16. doi: 10.1016/j.cell.2016.09.035. Epub 2016 Oct 13.

The Landscape of Mouse Meiotic Double-Strand Break Formation, Processing, and Repair.

Author information

1
Molecular Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
2
Molecular Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Memorial Sloan Kettering Cancer Center, Howard Hughes Medical Institute, New York, NY 10065, USA.
3
Molecular Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Tri-Institutional Training Program in Computational Biology and Medicine, Weill Cornell Medical College, New York, NY 10065, USA.
4
Molecular Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Weill Cornell Graduate School of Medical Sciences, New York, NY 10065, USA.
5
Bioinformatics Core, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
6
Weill Cornell Graduate School of Medical Sciences, New York, NY 10065, USA; Developmental Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. Electronic address: m-jasin@ski.mskcc.org.
7
Molecular Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Memorial Sloan Kettering Cancer Center, Howard Hughes Medical Institute, New York, NY 10065, USA; Weill Cornell Graduate School of Medical Sciences, New York, NY 10065, USA. Electronic address: s-keeney@ski.mskcc.org.

Abstract

Heritability and genome stability are shaped by meiotic recombination, which is initiated via hundreds of DNA double-strand breaks (DSBs). The distribution of DSBs throughout the genome is not random, but mechanisms molding this landscape remain poorly understood. Here, we exploit genome-wide maps of mouse DSBs at unprecedented nucleotide resolution to uncover previously invisible spatial features of recombination. At fine scale, we reveal a stereotyped hotspot structure-DSBs occur within narrow zones between methylated nucleosomes-and identify relationships between SPO11, chromatin, and the histone methyltransferase PRDM9. At large scale, DSB formation is suppressed on non-homologous portions of the sex chromosomes via the DSB-responsive kinase ATM, which also shapes the autosomal DSB landscape at multiple size scales. We also provide a genome-wide analysis of exonucleolytic DSB resection lengths and elucidate spatial relationships between DSBs and recombination products. Our results paint a comprehensive picture of features governing successive steps in mammalian meiotic recombination.

KEYWORDS:

DNA damage; DNA repair; PRDM9; SPO11; chromatin; double-strand break; homologous recombination; meiosis; mouse; resection

PMID:
27745971
PMCID:
PMC5117687
DOI:
10.1016/j.cell.2016.09.035
[Indexed for MEDLINE]
Free PMC Article

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