MLH1 IS UNIQUE AMONG MISMATCH REPAIR PROTEINS IN ITS ABILITY TO PROMOTE CROSSING-OVER DURING MEIOSIS

In eukaryotes, homologs of the bacterial MutS and MutL proteins functi on in DNA mismatch repair and recombination pathways. The mutL homolog MLH1 is required for nuclear mismatch repair. Previously, cytological analysis of MLH1-deficient mice has implied a role for Mlh1 in crossi ng-over during meiosis. Here we demonstrate that Saccharomyces cerevis iae diploids containing a deletion of MLH1 have reduced crossing-over in addition to a deficiency in the repair of mismatched DNA during mei osis. Absence of either of the meiosis-specific mutS homologs Msh4 or Msh5 results in a similar reduction in crossing-over. Analysis of an m lh1 msh4 double mutant suggests that both genes act in the same pathwa y to promote crossing-over. All genetic markers analyzed in mlh1 mutan ts display elevated frequencies of non-Mendelian segregation. Most of these events are postmeiotic segregations that represent unrepaired he teroduplex. These data suggest that either restorational repair is fre quent or heteroduplex tracts are shorter in wild-type cells. Compariso n of mlh1 segregation data with that of pms1, msh2, msh3, and msh6 mut ants show that the ability to promote crossing-over is unique to MLH1. Taken together these observations indicate that both crossing-over an d gene conversion require MutS and MutL functions and that Mlh1 repres ents an overlap between these two pathways. Models of Mlh1 function ar e discussed.