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.
|Ucisik-Akkaya, Esma; Leatherwood, Janet K; Neiman, Aaron M (2014) A genome-wide screen for sporulation-defective mutants in Schizosaccharomyces pombe. G3 (Bethesda) 4:1173-82|
|Berchowitz, Luke E; Gajadhar, Aaron S; van Werven, Folkert J et al. (2013) A developmentally regulated translational control pathway establishes the meiotic chromosome segregation pattern. Genes Dev 27:2147-63|
|Lo, Hsiao-Chi; Kunz, Ryan C; Chen, Xiangyu et al. (2012) Cdc7-Dbf4 is a gene-specific regulator of meiotic transcription in yeast. Mol Cell Biol 32:541-57|
|Yuan, Hua; Rossetto, Dorine; Mellert, Hestia et al. (2012) MYST protein acetyltransferase activity requires active site lysine autoacetylation. EMBO J 31:58-70|
|Yu, Yao; Srinivasan, Madhusudhan; Nakanishi, Shima et al. (2011) A conserved patch near the C terminus of histone H4 is required for genome stability in budding yeast. Mol Cell Biol 31:2311-25|
|Neiman, Aaron M (2011) Sporulation in the budding yeast Saccharomyces cerevisiae. Genetics 189:737-65|
|Chen, Huei-Mei; Neiman, Aaron M (2011) A conserved regulatory role for antisense RNA in meiotic gene expression in yeast. Curr Opin Microbiol 14:655-9|
|Srinivasan, Madhusudhan; Mehta, Preeti; Yu, Yao et al. (2011) The highly conserved KEOPS/EKC complex is essential for a universal tRNA modification, t6A. EMBO J 30:873-81|
|Yu, Yao; Neiman, Aaron M; Sternglanz, Rolf (2010) The JmjC domain of Gis1 is dispensable for transcriptional activation. FEMS Yeast Res 10:793-801|