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G3 (Bethesda). 2019 Jun 5;9(6):1839-1850. doi: 10.1534/g3.119.400074.

Mutation of the ATPase Domain of MutS Homolog-5 (MSH5) Reveals a Requirement for a Functional MutSγ Complex for All Crossovers in Mammalian Meiosis.

Author information

1
Department of Biomedical Sciences and Center for Reproductive Genomics, Cornell University, Ithaca, NY 14853.
2
Department of Cell Biology, Albert Einstein College of Medicine, Bronx, NY 10461.
3
Department of Systems and Computational Biology, Albert Einstein College of Medicine, Bronx, NY 10461.
4
Department of Cell Biology, Albert Einstein College of Medicine, Bronx, NY 10461 paula.cohen@cornell.edu winfried.edelmann@einstein.yu.edu.
5
Department of Biomedical Sciences and Center for Reproductive Genomics, Cornell University, Ithaca, NY 14853 paula.cohen@cornell.edu winfried.edelmann@einstein.yu.edu.

Abstract

During meiosis, induction of DNA double strand breaks (DSB) leads to recombination between homologous chromosomes, resulting in crossovers (CO) and non-crossovers (NCO). In the mouse, only 10% of DSBs resolve as COs, mostly through a class I pathway dependent on MutSγ (MSH4/ MSH5) and MutLγ (MLH1/MLH3), the latter representing the ultimate marker of these CO events. A second Class II CO pathway accounts for only a few COs, but is not thought to involve MutSγ/ MutLγ, and is instead dependent on MUS81-EME1. For class I events, loading of MutLγ is thought to be dependent on MutSγ, however MutSγ loads very early in prophase I at a frequency that far exceeds the final number of class I COs. Moreover, loss of MutSγ in mouse results in apoptosis before CO formation, preventing the analysis of its CO function. We generated a mutation in the ATP binding domain of Msh5 (Msh5GA ). While this mutation was not expected to affect MutSγ complex formation, MutSγ foci do not accumulate during prophase I. However, most spermatocytes from Msh5GA/GA mice progress to late pachynema and beyond, considerably further than meiosis in Msh5-/- animals. At pachynema, Msh5GA/GA spermatocytes show persistent DSBs, incomplete homolog pairing, and fail to accumulate MutLγ. Unexpectedly, Msh5GA/GA diakinesis-staged spermatocytes have no chiasmata at all from any CO pathway, indicating that a functional MutSγ complex is critical for all CO events regardless of their mechanism of generation.

KEYWORDS:

MutS homolog; crossing over; crossover designation; homologous recombination; meiosis; mouse; prophase I

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