Mutl homologs in yeast and mice

In yeast and mammalian cells MutL-like proteins function as heterodimers in mismatch repair to reduce mutation and to aid the recombination process. Using molecular genetic and biochemical techniques we are performing structure/function studies on the MutL proteins of yeast. We have identified regions of the MLH1 and PMS1 proteins necessary for heterodimerization. In addition, we have identified regions that appear to interact with other proteins important in the repair process. Using gene targeting in mouse embryonic stem cells, we have derived mice with null mutation in MLH1 and PMS2. In these mismatch repair deficient mice we have observed microsatellite instability in every tissue examined including the male germline, spleen, tail and tumor DNA. Furthermore, PMS2-deficient animals are prone to lymphomas and sarcomas. Of particular interest, MLH1- and PMS2-deficiency result in male infertility. In the PMS2-deficient animals the infertility is associated with abnormal chromosome pairing in meiosis. Further studies on the basis of these meiotic effects will be discussed.