Eukaryotic organisms utilize two types of cell division. Mitosis creates genetically identical daughter cells, thereby providing the raw material for growth and differentiation. Meiosis, in contrast, divides the chromosome number of cells in half, producing haploid gametes containing new combinations of alleles. This reduction is essential in keeping the chromosome number constant when two gametes fuse at fertilization. Mitosis and meiosis share many features in common: for example, chromosomes are segregated using microtubule based spindles, sister chromatids are held together by cohesins, and destruction of cohesins occurs via the same proteolytic machinery. Several meiosis-specific processes have evolved, however, to allow two divisions to occur after a single round of DNA replication such that homologous chromosomes, instead of sister chromatids, disjoin to opposite poles at Meiosis I. These include the connection of homologous chromosomes by a combination of crossing over and cohesion, the temporally distinct two step removal of cohesins at Meiosis I and Meiosis II and the mono-orientation of sister kinetochores at Meiosis I. Recent work has shown that these meiosis-specific processes result from the interplay between meiosis-specific proteins and mitotic cell cycle kinases such as CDK, Cdc5 and Cdc7. Using an analog sensitive conditional allele of CDC7, cdc7-as, my lab has shown that CDC7 is essential for meiotic recombination, mono-orientation of sister kinetochores and meiotic progression. The purpose of this grant is to use biochemical, genetic and genomic approaches to understand how Cdc7 regulates meiotic processes at the molecular level.
In Aim 1, we will identify meiotic substrates of Cdc7 using novel strategies recently developed for use with analog sensitive kinases.
In Aim 2, we will investigate how Cdc7 regulates the expression of NDTSO, a meiosis-specific transcription factor that acts a molecular switch to allow exit from pachytene, meiotic progression and differentiation of haploid products into spores.
Failures in meiosis result in infertility and birth defects such as Down syndrome. Proper meiotic chromosome segregation requires interplay between a conserved cell cycle kinase and meiosis-specific proteins. This grant will define the molecular role of this kinase in proper meiotic chromosome behavior ? knowledge that may ultimately lead to the diagnosis and/or prevention of certain types of infertility, birth defects and even cancer.
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