Control of DNA Replication and Cell Division

DNA 复制和细胞分裂的控制

• 批准号: 6687040
• 负责人: TERESA S WANG
• 金额: $ 37.52万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1991
• 资助国家: 美国
• 起止时间: 1991-05-01 至 2008-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6687040
• 关键词: DNA directed DNA polymerase; DNA repair; DNA replication; Saccharomyces; cell cycle; cell growth regulation; fungal genetics; gene expression; gene mutation; phosphorylation; proliferating cell nuclear antigen

DESCRIPTION (provided by applicant): The overall goal of this research program is to investigate how eukaryotic cells respond to replication perturbations in order to maintain the genomic stability by using fission yeast as the model organism. When faced with chromosomal perturbations, eukaryotic organisms activate a complex set of signal transduction response pathways called checkpoints to regulate cell-cycle transition, to facilitate DNA repair or in some cases to induce apoptosis. Failure of these responses results in genomic instability, which can promote tumor development. In addition, cells have evolved other processes to deal with the genomic perturbations to restart replication. Cells can use a large repertoire of translesional DNA polymerases to perform either error-free or error-prone synthesis, which has the potential to generate point mutations and single base frameshifts. Cells can also use recombination/repair to restart replication, which has the potential of inducing deletion mutations in cells. Mutations in replication genes often induce a mutator phenotype characterized by deletion mutations and point mutations. Little is known about how checkpoints respond to the replication perturbations caused by replication mutants. Our recent studies have shown that mutations in checkpoint genes significantly affect the mutator phenotype in the replication mutants. These findings have led us to hypothesize: In response to genomic perturbation, the checkpoint-clamp recruits translesional polymerases onto chromatin for mutagenic synthesis which generates point mutations and recruits recombination/repair factor(s) to promote deletion mutations. In contrast, Cds1 kinase regulates the recombination/repair factors to prevent deletion mutations. Together these processes will facilitate recovery from a stalled replication to restart DNA replication. Specific Aims proposed to test this hypothesis are: (1). How do the checkpoint clamp and/or checkpoint-clamp-loader recruit translesional polymerases for mutagenic synthesis in order to restart a stalled replication fork? (2). How does the checkpoint effector kinase Cds1 function in preventing deletion mutations to occur, and does the checkpoint clamp/clamp-loader promote deletion mutations in cells to prevent replication fork from collapse and to restart a stalled replication fork?

描述（由申请人提供）：