title: Meiotic arrest and aneuploidy in MLH3-deficient mice.
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 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.
authors.affiliation: Division of Hematology-Oncology, Department of Medicine, University of California, Irvine, California 92697, USA. slipkin@uci.edu
authors.forename: Steven M
authors.initials: SM
authors.lastname: Lipkin
authors.forename: Peter B
authors.initials: PB
authors.lastname: Moens
authors.forename: Victoria
authors.initials: V
authors.lastname: Wang
authors.forename: Michelle
authors.initials: M
authors.lastname: Lenzi
authors.forename: Dakshine
authors.initials: D
authors.lastname: Shanmugarajah
authors.forename: Abigail
authors.initials: A
authors.lastname: Gilgeous
authors.forename: James
authors.initials: J
authors.lastname: Thomas
authors.forename: Jun
authors.initials: J
authors.lastname: Cheng
authors.forename: Jeffrey W
authors.initials: JW
authors.lastname: Touchman
authors.forename: Eric D
authors.initials: ED
authors.lastname: Green
authors.forename: Pam
authors.initials: P
authors.lastname: Schwartzberg
authors.forename: Francis S
authors.initials: FS
authors.lastname: Collins
authors.forename: Paula E
authors.initials: PE
authors.lastname: Cohen
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000251:Adenosine Triphosphatases / Q000235:genetics / Q000378:metabolism; D000782:Aneuploidy; D000818:Animals; D017209:Apoptosis / Q000235:genetics; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism; D002875:Chromosomes / Q000235:genetics / Q000378:metabolism; D045643:DNA Repair Enzymes; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D005091:Exons; D005260:Female; D005307:Fertilization in Vitro; D007247:Infertility, Female / Q000235:genetics*; D008297:Male; D008540:Meiosis; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D018895:Microsatellite Repeats; D000070976:Mismatch Repair Endonuclease PMS2; D008969:Molecular Sequence Data; D000070957:MutL Protein Homolog 1; D000070956:MutL Proteins; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism; D009687:Nuclear Proteins; D009865:Oocytes / Q000473:pathology; D017421:Sequence Analysis; D013090:Spermatocytes / Q000378:metabolism; D013737:Testis / Q000002:abnormalities
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D004268:DNA-Binding Proteins; C501486:MLH1 protein, human; C501485:Mlh1 protein, mouse; C492407:Mlh3 protein, mouse; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D000251:Adenosine Triphosphatases; C499533:Pms2 protein, mouse; D000070976:Mismatch Repair Endonuclease PMS2; D000070957:MutL Protein Homolog 1; D000070956:MutL Proteins; D045643:DNA Repair Enzymes