This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor the Center, which is not necessarily the institution for the investigator.For meiosis to succeed a complicated series of processes must occur including cell cycle progression, recombination, chromosome segregation and cell division. Phenotype-driven mutagenic screens have generated the mutation mei4. Meiosis in mei4/mei4 homozygotes fails due to reduced recombination and production of aneuploid gametes. The mismatch repair protein, Mlh1, fails to load onto meiotic chromosomes during prophase I of meiosis in mei4/mei4 animals. We have identified the causative mutation behind the mei4 phenotype in a putative E3 ligase that functions to regulate cyclin degradation. We will characterize the mutant mei4 allele in the context of meiotic DNA repair and cell cycle biology via the following specific aims and strategies:(1) mRNA and protein expression profiling, (2) protein-protein interaction studies, (3) immunocytochemistry of protein constituents at recombination sites. This work has significant health relatedness as mismatch repair proteins are associated with colorectal cancer (HNPCC), E3 ligases and their substrates have been implicated in several cancers (including inherited breast cancer) and in neurodegenerative disorders, and aneuploidy is a major source of birth defects. The characterization of mei4 will not only contribute to our understanding of the basic molecular biology of meiosis but will also increase our knowledge of important human health issues.
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