This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Genome instability is a hallmark of cancer. Cells are constantly exposed to various exogenous and endogenous agents that threaten genome stability by damaging DNA or affecting DNA replication. However, cells have devised various means such as DNA damage and replication checkpoints, and DNA repair to maintain genome stability. We are studying the role of DNA replication in the maintenance of genome stability using budding yeast as a paradigm. Defects in genes involved in DNA replication and repair show sensitivity to anti-neoplastic agents such as hydroxyurea (HU) and methyl-methane sukfonate (MMS) that are known to impede replication forks. Interestingly recent works from various laboratories and our own unpublished data show that genes involved in many other pathways including sphingolipid pathway also play significant roles in resistance to these agents suggesting that sphingolipid pathway genes play role in genome stability. To understand the mechanism of action of the sphingolipid genes in genome stability we want to conduct the following studies: 1. Identify all the sphingolipid genes that confer resistance or sensitivity to HU and MMS. Determine their possible roles in replication checkpoint, DNA damage checkpoint and DNA repair. 2. We shall study the mechanism of action inositol phospholipase C gene ISC1 in HU/MMS resistance. Defect in ISC1 causes G2/M arrest in HU. We shall dissect the checkpoint pathway in isc1D cells. 3. Protein ubiquitination plays role in DNA repair. Isc1 is ubiquitinated;it genetically interacts with several DNA repair proteins. We shall determine the role of Isc1 in DNA repair.
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