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Localization of MMR proteins on meiotic chromosomes in mice indicates distinct functions during prophase I

¹ Department of Molecular Genetics, Albert Einstein College of Medicine, Bronx, NY 10461
² Department of Anatomy and Structural Biology, Albert Einstein College of Medicine, Bronx, NY 10461
³ Department of Medicine, Albert Einstein College of Medicine, Bronx, NY 10461
⁴ Department of Cell Biology, Albert Einstein College of Medicine, Bronx, NY 10461
⁵ Department of Hematology, University of California, Irvine, Irvine, CA 92697
⁶ Molecular and Medical Genetics, Oregon Health Sciences University, Portland, OR 97239

Correspondence to P.E. Cohen: pc242{at}cornell.edu

Mammalian MutL homologues function in DNA mismatch repair (MMR) after replication errors and in meiotic recombination. Both functions are initiated by a heterodimer of MutS homologues specific to either MMR (MSH2–MSH3 or MSH2–MSH6) or crossing over (MSH4–MSH5). Mutations of three of the four MutL homologues (Mlh1, Mlh3, and Pms2) result in meiotic defects. We show herein that two distinct complexes involving MLH3 are formed during murine meiosis. The first is a stable association between MLH3 and MLH1 and is involved in promoting crossing over in conjunction with MSH4–MSH5. The second complex involves MLH3 together with MSH2–MSH3 and localizes to repetitive sequences at centromeres and the Y chromosome. This complex is up-regulated in Pms2^–/– males, but not females, providing an explanation for the sexual dimorphism seen in Pms2^–/– mice. The association of MLH3 with repetitive DNA sequences is coincident with MSH2–MSH3 and is decreased in Msh2^–/– and Msh3^–/– mice, suggesting a novel role for the MMR family in the maintenance of repeat unit integrity during mammalian meiosis.

P.E. Cohen's present address is Dept. of Biomedical Sciences, Cornell University, Ithaca, NY 14853.

Abbreviations used in this paper: DDB, double dense body; dHJ, double Holliday junction; DSB, DNA double strand break; MLH1 and 3, MutL homologue 1 and 3; MMR, mismatch repair; MN, meiotic nodule; MSH2–6, MutS homologue; PAR, pseudoautosomal region; PMS2, postmeiotic segregation 2; TNR, trinucleotide repeat.

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