title: MUS81 generates a subset of MLH1-MLH3-independent crossovers in mammalian meiosis.
abstract: Two eukaryotic pathways for processing double-strand breaks (DSBs) as crossovers have been described, one dependent on the MutL homologs Mlh1 and Mlh3, and the other on the structure-specific endonuclease Mus81. Mammalian MUS81 has been implicated in maintenance of genomic stability in somatic cells; however, little is known about its role during meiosis. Mus81-deficient mice were originally reported as being viable and fertile, with normal meiotic progression; however, a more detailed examination of meiotic progression in Mus81-null animals and WT controls reveals significant meiotic defects in the mutants. These include smaller testis size, a depletion of mature epididymal sperm, significantly upregulated accumulation of MLH1 on chromosomes from pachytene meiocytes in an interference-independent fashion, and a subset of meiotic DSBs that fail to be repaired. Interestingly, chiasmata numbers in spermatocytes from Mus81-/- animals are normal, suggesting additional integrated mechanisms controlling the two distinct crossover pathways. This study is the first in-depth analysis of meiotic progression in Mus81-nullizygous mice, and our results implicate the MUS81 pathway as a regulator of crossover frequency and placement in mammals.
authors.affiliation: Department of Biomedical Sciences, Cornell University, Ithaca, New York, United States of America.
authors.forename: J Kim
authors.initials: JK
authors.lastname: Holloway
authors.forename: James
authors.initials: J
authors.lastname: Booth
authors.forename: Winfried
authors.initials: W
authors.lastname: Edelmann
authors.forename: Clare H
authors.initials: CH
authors.lastname: McGowan
authors.forename: Paula E
authors.initials: PE
authors.lastname: Cohen
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism; D003434:Crossing Over, Genetic; D053903:DNA Breaks, Double-Stranded; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D004720:Endonucleases / Q000235:genetics* / Q000378:metabolism; D005260:Female; D005455:Fluorescent Antibody Technique; D006720:Homozygote; D008297:Male; D008540:Meiosis / Q000235:genetics*; D051379:Mice; D018345:Mice, Knockout; D000070957:MutL Protein Homolog 1; D000070956:MutL Proteins; D009154:Mutation; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D009865:Oocytes / Q000166:cytology / Q000378:metabolism; D013076:Sperm Count; D013737:Testis / Q000166:cytology / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D004268:DNA-Binding Proteins; C501485:Mlh1 protein, mouse; C492407:Mlh3 protein, mouse; D009687:Nuclear Proteins; D004720:Endonucleases; C498773:Mus81 protein, mouse; D000070957:MutL Protein Homolog 1; D000070956:MutL Proteins
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