![]() ![]() The mammalian meiotic MMR complex, consisting of MSH4, MSH5, MLH1, and MLH3, has been implicated in the processing of DNA double strand breaks (DSB) through the double Holliday junction (dHJ) recombination intermediate repair pathway that results in reciprocal crossover events between parental homologous chromosomes ( Ross-Macdonald and Roeder, 1994 Hollingsworth et al., 1995 Novak et al., 2001 Borner et al., 2004 Hoffmann and Borts, 2004 Surtees et al., 2004). 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. This complex is up-regulated in Pms2 − / − males, but not females, providing an explanation for the sexual dimorphism seen in Pms2 − / − mice. The second complex involves MLH3 together with MSH2–MSH3 and localizes to repetitive sequences at centromeres and the Y chromosome. The first is a stable association between MLH3 and MLH1 and is involved in promoting crossing over in conjunction with MSH4–MSH5. We show herein that two distinct complexes involving MLH3 are formed during murine meiosis. Mutations of three of the four MutL homologues ( Mlh1, Mlh3, and Pms2) result in meiotic defects. Both functions are initiated by a heterodimer of MutS homologues specific to either MMR (MSH2–MSH3 or MSH2–MSH6) or crossing over (MSH4–MSH5). Mammalian MutL homologues function in DNA mismatch repair (MMR) after replication errors and in meiotic recombination.
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