Research Focus
- Investigation of how MutL homologs interact with each other to regulate/maintain/stabilize recombination sites
- Dual roles for MutS homologs - how do protein-protein interactions determine the function of these complexes during meiosis
- Generation of in vivo models for meiotic analysis
- Generation of meiosis-specific mutations in key recombination genes
- Checkpoint regulatory differences between male and females meiosis
- Investigation of the etiology of meiotic disruption in aging females
- Human meiosis - regulation by mismatch repair proteins
- Proteomic and genomic analysis of meiotic prophase in humans and mice
- Repeat instability in the germline
The role of DNA mismatch repair proteins in meiosis and recombination: an evolutionarily conserved function for the MutHLS gene family
The regulation of mammalian meiosis has become a major focus for research in recent years, in part due to the increased availability of mouse mutants affecting meiotic recombination and gametogenesis. This research is of particular interest to those seeking to improve fertility rates in the human population and to understand the decline in fertility of older women. Our lab studies the role of DNA repair proteins in mammalian meiosis and germ cell development. The DNA mismatch repair (MMR) proteins are highly conserved throughout evolution, both at the level of the gene and at the level of the amino acid sequence. The function of these gene products is also highly conserved from yeast through to humans, with homologs being identified in yeast, flies, worms, plants and mammals. Recently, we have shown that the human MLH3 gene can rescue the infertility phenotype exhibited by mice harboring a mutation in the Mlh3 gene. This important observation indicates that the mouse and human genes are functionally equivalent, as suggested by their high degree of sequence similarity.
The main questions we are trying to ask relate to why this group of genes should be so highly conserved between species, how meiotic progression is regulated in mammalian germ cells, whether this regulation differs between males and females, and how the meiotic progress is monitored with respect to germ cell development and viability. Using these studies we hope to define the regulatory mechanisms that control meiotic progression in mammals, and thereby to gain a better understanding of why and how meiosis fails in humans and other mammalian species.
The importance of the DNA mismatch repair pathway was underscored in 1993 when scientists determined that mutations in several MMR genes results in the cancer predisposition syndrome, human non-polyposis colorectal cancer (HNPCC). HNPCC, which accounts for 5% of all colorectal cancer cases, is a highly penetrant autosomal dominant disorder characterized by early onset (40-50 years of age) cancers of the colon, enddometrium, ovary, stomach and small intestine. In light of their importance, therefore, a major focus of research here at Einstein has been the role of the MMR genes in the genesis of colorectal (and other) cancer. Our research is geared towards examining the physiological function of these gene products in mammals and, as such, serves to compliment the tumorigenesis studies being undertaken by our collaborators. Thus, in addition to the questions we are asking with resepect to human fertility and chromosomal abnormalities, a major focus in the lab is to elaborate the function of these gene products during normal cell activity, and thereby provide a greater insight into how/why such processes become disrupted during tumorigenesis.
Current Projects in the lab include:
For further details, contact any of the lab members.