Prdm9 and Meiotic Cohesin Proteins Cooperatively Promote DNA Double-Strand Break Formation in Mammalian Spermatocytes.

Document Type

Article

Publication Date

3-18-2019

Keywords

JMG

JAX Source

Curr Biol 2019 Mar 18; 29(6):1002-1018.e7

Volume

29

Issue

6

First Page

1002

Last Page

1018

ISSN

1879-0445

PMID

30853435

DOI

https://doi.org/10.1016/j.cub.2019.02.007

Grant

GM99640,CA034196,19042802-15-3 (JAX Scholar award),H007065

Abstract

Meiotic recombination is required for correct segregation of chromosomes to gametes and to generate genetic diversity. In mice and humans, DNA double-strand breaks (DSBs) are initiated by SPO11 at recombination hotspots activated by PRDM9-catalyzed histone modifications on open chromatin. However, the DSB-initiating and repair proteins are associated with a linear proteinaceous scaffold called the chromosome axis, the core of which is composed of cohesin proteins. STAG3 is a stromalin subunit common to all meiosis-specific cohesin complexes. Mutations of meiotic cohesin proteins, especially STAG3, perturb both axis formation and recombination in the mouse, prompting determination of how the processes are mechanistically related. Protein interaction and genetic analyses revealed that PRDM9 interacts with STAG3 and REC8 in cooperative relationships that promote normal levels of meiotic DSBs at recombination hotspots in spermatocytes. The efficacy of the Prdm9-Stag3 genetic interaction in promoting DSB formation depends on PRDM9-mediated histone methyltransferase activity. Moreover, STAG3 deficiency has a major effect on DSB number even in the absence of PRDM9, showing that its role is not restricted to canonical PRDM9-activated hotspots. STAG3 and REC8 promote axis localization of the DSB-promoting proteins HORMAD1, IHO1, and MEI4, as well as SPO11 activity. These results establish that PRDM9 and axis-associated cohesin complexes together coordinate and facilitate meiotic recombination by recruiting key proteins for initiation of DSBs, thereby associating activated hotspots with DSB-initiating complexes on the axis.

Comments

We thank three anonymous reviewers for their helpful comments. Further, we thank Drs. Ewelina Bolcun-Filas, Beth Dumont, and Ken Paigen for discussion throughout this work and for their thoughtful comments on the manuscript. We also thank all members of the Handel, Paigen, and Petkov labs for insightful discussions and suggestions. We are appreciative of The Jackson Laboratory Scientific Services, including the Histology core, the Microscopy core, Genome Technologies, Genetic Engineering Technology, Mouse Resources, and Computational Sciences (specifically Vivek Philip and Tim Stearns) for their expertise and help during this project. We thank the Knockout mouse project (KOMP2) at the Jackson Laboratory for providing mice. We thank Drs. Michiel Boekhout, Kevin Brick, Bernard de Massy, Yasuhiro Fujiwara, Rolf Jessberger, Scott Keeney, Attila Toth, and Yoshinori Watanabe for sharing their antibody resources and help during this project.

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