MLH1 Mutations Differentially Affect Meiotic Functions in Saccharomyces cerevisiae
a Department of Biochemistry, University of Oxford, Oxford OX1 3Q, United Kingdom,b Department of Genetics, Leicester University, Leicester LE1 7RH, United Kingdom7wl, http://www.100md.com
c Laboratory of Molecular Genetics, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 277097wl, http://www.100md.com
ABSTRACT7wl, http://www.100md.com
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.7wl, http://www.100md.com
THE mismatch repair system plays a number of roles in maintaining genome stability. During mitosis it primarily ensures avoidance of mutations and inappropriate recombination events (reviewed in HARFE and JINKS-ROBERTSON 2000 ) while during meiosis it is involved in heteroduplex repair, crossing over, chromosome segregation, and avoidance of inappropriate recombination (reviewed in BORTS et al. 2000 ). Mismatch repair proteins function as dimers. MutS and MutL in bacteria form homodimers while their eukaryotic homologs form heterodimers. There are six MutS homologs, MSH1–6, and four MutL homologs, MLH1–3 and PMS1 (PMS2 in humans). Mutation avoidance is accomplished by mispair recognition by Msh2p/Msh6p (MutS(Eva R. Hoffmann Polina V. Shcherbakova Thomas A. Kunkel and Rhona H. Borts)
c Laboratory of Molecular Genetics, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 277097wl, http://www.100md.com
ABSTRACT7wl, http://www.100md.com
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.7wl, http://www.100md.com
THE mismatch repair system plays a number of roles in maintaining genome stability. During mitosis it primarily ensures avoidance of mutations and inappropriate recombination events (reviewed in HARFE and JINKS-ROBERTSON 2000 ) while during meiosis it is involved in heteroduplex repair, crossing over, chromosome segregation, and avoidance of inappropriate recombination (reviewed in BORTS et al. 2000 ). Mismatch repair proteins function as dimers. MutS and MutL in bacteria form homodimers while their eukaryotic homologs form heterodimers. There are six MutS homologs, MSH1–6, and four MutL homologs, MLH1–3 and PMS1 (PMS2 in humans). Mutation avoidance is accomplished by mispair recognition by Msh2p/Msh6p (MutS(Eva R. Hoffmann Polina V. Shcherbakova Thomas A. Kunkel and Rhona H. Borts)