Role of DNA polymerases in chromosome stability control

非整倍体是人类癌症中几乎无处不在的特征。研究染色体不稳定的分子机制对于制定有效的癌症预防和治疗策略具有重要意义。该项目的长期目标是确定遗传和环境因素影响染色体保真度的机制。 种族隔离。这一建议的基本假设是：1)编码DNA聚合酶的基因的某些突变可通过扰乱DNA合成和染色体分离的协调而导致染色体丢失和不分离的增加，以及2)这些突变体中的染色体不稳定性可因暴露于环境遗传毒物而进一步增加。这些假设将通过追求以下具体目标来检验：(1)发展 一种新的定量分析酵母染色体分离的新系统，它允许直接选择非分离事件，(2)识别编码DNA聚合酶的基因突变，这些突变将导致自发或环境遗传毒物诱导的染色体错误分离的增加，以及(3)研究目标2中确定的突变体中染色体分离缺陷的机制。紫外线照射，烷化剂， 将测试氧化应激和拟辐射化学物质博莱霉素对染色体稳定性的影响。这些研究将为鉴定与诱导人类癌细胞非整倍体有关的人类基因和环境因素提供基础。

Aneuploidy is a nearly ubiquitous feature of human cancers. Investigation of the molecular mechanisms of chromosome instability is important for the development of effective strategies for cancer prevention and therapy. The long-term objective of this project is to determine the mechanisms by which genetic and environmental factors affect the fidelity of chromosome segregation. The basic hypotheses of this proposal are that: 1) certain mutations in genes encoding DNA polymerases can cause increased chromosome loss and nondisjunction by disrupting coordination of DNA synthesis and chromosome segregation, and 2) chromosome instability in such mutants can be further increased by exposure to environmental genotoxicants. These hypotheses will be tested by pursuing the following specific aims: (1) develop a novel system for quantitative analysis of chromosome missegregation in yeast that allows direct selection for nondisjunction events, (2) identify mutations in genes encoding DNA polymerases that would lead to increase in spontaneous or environmental genotoxicant-induced chromosome missegregation, and (3) investigate the mechanisms of chromosome segregation defects in mutants identified in aim 2. The effects of UV-irradiation, alkylating agents, oxidative stress and the radiomimetic chemical bleomycin on chromosome stability will be tested. These studies will provide the basis for identification of human genes and environmental factors involved in induction of aneuploidy in human cancer cells.