Distinct functions of MLH3 at recombination hot spots in the mouse.
The four mammalian MutL homologs (MLH1, MLH3, PMS1, and PMS2) participate in a variety of events, including postreplicative DNA repair, prevention of homeologous recombination, and crossover formation during meiosis. In this latter role, MLH1-MLH3 heterodimers predominate and are essential for prophase I progression. Previous studies demonstrated that mice lacking Mlh1 exhibit a 90% reduction in crossing over at the Psmb9 hot spot while noncrossovers, which do not result in exchange of flanking markers but arise from the same double-strand break event, are unaffected. Using a PCR-based strategy that allows for detailed analysis of crossovers and noncrossovers, we show here that Mlh3(-/-) exhibit a 85-94% reduction in the number of crossovers at the Psmb9 hot spot. Most of the remaining crossovers in Mlh3(-/-) meiocytes represent simple exchanges similar to those seen in wild-type mice, with a small fraction (6%) representing complex events that can extend far from the initiation zone. Interestingly, we detect an increase of noncrossovers in Mlh3(-/-) spermatocytes. These results suggest that MLH3 functions predominantly with MLH1 to promote crossovers, while noncrossover events do not require these activities. Furthermore, these results indicate that approximately 10% of crossovers in the mouse are independent of MLH3, suggesting the existence of alternative crossover pathways in mammals.
Svetlanov
Anton
A
Department of Biomedical Sciences, Cornell University, Ithaca, New York 14850, USA.
Baudat
Frederic
F
Cohen
Paula E
PE
de Massy
Bernard
B
D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism*; D002874:Chromosome Mapping; D003434:Crossing Over, Genetic / Q000235:genetics; D005260:Female; D051379:Mice; D000070956:MutL Proteins; D009866:Oogenesis / Q000235:genetics; D010053:Ovary / Q000378:metabolism; D011995:Recombination, Genetic / Q000235:genetics*; D013091:Spermatogenesis / Q000235:genetics
D002352:Carrier Proteins; C492407:Mlh3 protein, mouse; D000070956:MutL Proteins