1. Abstract 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 ... 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.
PMID: [18430927]
2. 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 meiosis. The pathway in eukaryotes consists of ... MutL homolog 3 (Mlh3) is a member of a family of proteins conserved during evolution and having dual roles in DNA mismatch repair and meiosis. 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 errors, and two others, Msh4 and Msh5, have specific roles in meiosis. 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 mice. To assess the role of Mlh3 in mammalian meiosis, we have generated and characterized Mlh3(-/-) mice. 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.
PMID: [12091911]
S. M. Lipkin, P. B. Moens, V. Wang, M. Lenzi, D. Shanmugarajah, A. Gilgeous, J. Thomas, J. Cheng, J. W. Touchman, E. D. Green, P. Schwartzberg, F. S. Collins and P. E. Cohen (2002) Meiotic arrest and aneuploidy in MLH3-deficient mice. Nat Genet 31(4): 385-90. PMID: [12091911]
S. M. Lipkin, P. B. Moens, V. Wang, M. Lenzi, D. Shanmugarajah, A. Gilgeous, J. Thomas, J. Cheng, J. W. Touchman, E. D. Green, P. Schwartzberg, F. S. Collins and P. E. Cohen (2002) Meiotic arrest and aneuploidy in MLH3-deficient mice. Nat Genet 31(4): 385-90. PMID: [12091911]
S. M. Lipkin, P. B. Moens, V. Wang, M. Lenzi, D. Shanmugarajah, A. Gilgeous, J. Thomas, J. Cheng, J. W. Touchman, E. D. Green, P. Schwartzberg, F. S. Collins and P. E. Cohen (2002) Meiotic arrest and aneuploidy in MLH3-deficient mice. Nat Genet 31(4): 385-90. PMID: [12091911]
S. M. Lipkin, P. B. Moens, V. Wang, M. Lenzi, D. Shanmugarajah, A. Gilgeous, J. Thomas, J. Cheng, J. W. Touchman, E. D. Green, P. Schwartzberg, F. S. Collins and P. E. Cohen (2002) Meiotic arrest and aneuploidy in MLH3-deficient mice. Nat Genet 31(4): 385-90. PMID: [12091911]
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. Mlh3 is required for Mlh1 binding to meiotic chromosomes and localizes to meiotic chromosomes from the mid pachynema stage of prophase I.
