Abstract
MutL homolog 3 (Mlh3) is a member of a family of proteins conserved during evolution and having dual roles in DNA mismatch repair and meiosis1,2. The pathway in eukaryotes consists of the DNA-binding components, which are the homologs of the bacterial MutS protein (MSH 2–6), and the MutL homologs, which bind to the MutS homologs and are essential for the repair process. Three of the six homologs of MutS that function in these processes, Msh2, Msh3 and Msh6, are involved in the mismatch repair of mutations, frameshifts and replication errors2,3, and two others, Msh4 and Msh5, have specific roles in meiosis4,5,6,7,8,9,10. Of the four MutL homologs, Mlh1, Mlh3, Pms1 and Pms2, three are involved in mismatch repair and at least two, Pms2 and Mlh1, are essential for meiotic progression in both yeast and mice2,3,11,12,13,14. To assess the role of Mlh3 in mammalian meiosis, we have generated and characterized Mlh3−/− mice15. Here we show that Mlh3−/− mice are viable but sterile. Mlh3 is required for Mlh1 binding to meiotic chromosomes and localizes to meiotic chromosomes from the mid pachynema stage of prophase I. Mlh3−/− spermatocytes reach metaphase before succumbing to apoptosis, but oocytes fail to complete meiosis I after fertilization. Our results show that Mlh3 has an essential and distinct role in mammalian meiosis.
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Acknowledgements
We thank G. Elliott and A. Becker for help with mouse studies; M. Liskay and W. Edelmann for critically reading this manuscript; G. Enders for antibodies; and N. Kolas for discussions and advice. This work was supported by the Albert Einstein College of Medicine (P.E.C.), National Human Genome Research Institute intramural funds and New Faculty start-up funds through the University of California, Irvine (S.M.L.).
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Lipkin, S., Moens, P., Wang, V. et al. Meiotic arrest and aneuploidy in MLH3-deficient mice. Nat Genet 31, 385–390 (2002). https://doi.org/10.1038/ng931
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DOI: https://doi.org/10.1038/ng931
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