Localization of MMR proteins on meiotic chromosomes in mice indicates distinct functions during prophase I.
Mammalian MutL homologues function in DNA mismatch repair (MMR) after replication errors and in meiotic recombination. Both functions are initiated by a heterodimer of MutS homologues specific to either MMR (MSH2-MSH3 or MSH2-MSH6) or crossing over (MSH4-MSH5). Mutations of three of the four MutL homologues (Mlh1, Mlh3, and Pms2) result in meiotic defects. We show herein that two distinct complexes involving MLH3 are formed during murine meiosis. The first is a stable association between MLH3 and MLH1 and is involved in promoting crossing over in conjunction with MSH4-MSH5. The second complex involves MLH3 together with MSH2-MSH3 and localizes to repetitive sequences at centromeres and the Y chromosome. This complex is up-regulated in Pms2-/- males, but not females, providing an explanation for the sexual dimorphism seen in Pms2-/- mice. The association of MLH3 with repetitive DNA sequences is coincident with MSH2-MSH3 and is decreased in Msh2-/- and Msh3-/- mice, suggesting a novel role for the MMR family in the maintenance of repeat unit integrity during mammalian meiosis.
Kolas
Nadine K
NK
Department of Molecular Genetics, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
Svetlanov
Anton
A
Lenzi
Michelle L
ML
Macaluso
Frank P
FP
Lipkin
Steven M
SM
Liskay
R Michael
RM
Greally
John
J
Edelmann
Winfried
W
Cohen
Paula E
PE
D048868:Adaptor Proteins, Signal Transducing; D000251:Adenosine Triphosphatases / Q000235:genetics / Q000378:metabolism; D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D018797:Cell Cycle Proteins / Q000378:metabolism; D002503:Centromere / Q000235:genetics / Q000502:physiology / Q000648:ultrastructure; D045643:DNA Repair Enzymes / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D008297:Male; D008540:Meiosis; D049469:Meiotic Prophase I; D051379:Mice; D018345:Mice, Knockout; D016253:Microscopy, Immunoelectron; D000070976:Mismatch Repair Endonuclease PMS2; D000070957:MutL Protein Homolog 1; D000070956:MutL Proteins; D051718:MutS Homolog 2 Protein / Q000235:genetics / Q000378:metabolism*; D000074081:MutS Homolog 3 Protein; D009687:Nuclear Proteins / Q000378:metabolism; D011485:Protein Binding; D011506:Proteins / Q000235:genetics / Q000378:metabolism; D013090:Spermatocytes / Q000502:physiology / Q000648:ultrastructure; D014998:Y Chromosome / Q000235:genetics / Q000502:physiology* / Q000648:ultrastructure
D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; C501485:Mlh1 protein, mouse; C492407:Mlh3 protein, mouse; C089762:Msh3 protein, mouse; C502328:Msh4 protein, mouse; C512847:Msh5 protein, mouse; D000074081:MutS Homolog 3 Protein; D009687:Nuclear Proteins; D011506:Proteins; D000251:Adenosine Triphosphatases; C499533:Pms2 protein, mouse; D000070976:Mismatch Repair Endonuclease PMS2; C497173:Msh2 protein, mouse; D000070957:MutL Protein Homolog 1; D000070956:MutL Proteins; D051718:MutS Homolog 2 Protein; D045643:DNA Repair Enzymes