MLH1 mutations differentially affect meiotic functions in Saccharomyces cerevisiae.
To test whether missense mutations in the cancer susceptibility gene MLH1 adversely affect meiosis, we examined 14 yeast MLH1 mutations for effects on meiotic DNA transactions and gamete viability in the yeast Saccharomyces cerevisiae. Mutations analogous to those associated with hereditary nonpolyposis colorectal cancer (HNPCC) or those that reduce Mlh1p interactions with ATP or DNA all impair replicative mismatch repair as measured by increased mutation rates. However, their effects on meiotic heteroduplex repair, crossing over, chromosome segregation, and gametogenesis vary from complete loss of meiotic functions to no meiotic defect, and mutants defective in one meiotic process are not necessarily defective in others. DNA binding and ATP binding but not ATP hydrolysis are required for meiotic crossing over. The results reveal clear separation of different Mlh1p functions in mitosis and meiosis, and they suggest that some, but not all, MLH1 mutations may be a source of human infertility.
Hoffmann
Eva R
ER
Department of Biochemistry, University of Oxford, Oxford OX1 3Q, United Kingdom.
Shcherbakova
Polina V
PV
Kunkel
Thomas A
TA
Borts
Rhona H
RH
D048868:Adaptor Proteins, Signal Transducing; D000595:Amino Acid Sequence; D000782:Aneuploidy; D003434:Crossing Over, Genetic / Q000502:physiology; D004260:DNA Repair / Q000235:genetics / Q000502:physiology; D005656:Fungal Proteins / Q000235:genetics* / Q000378:metabolism; D008540:Meiosis / Q000235:genetics* / Q000502:physiology; D008969:Molecular Sequence Data; D000070957:MutL Protein Homolog 1; D009630:Nondisjunction, Genetic; D012441:Saccharomyces cerevisiae / Q000235:genetics* / Q000378:metabolism; D029701:Saccharomyces cerevisiae Proteins; D016415:Sequence Alignment
D048868:Adaptor Proteins, Signal Transducing; D005656:Fungal Proteins; C088859:MLH1 protein, S cerevisiae; D029701:Saccharomyces cerevisiae Proteins; D000070957:MutL Protein Homolog 1