PIK RELATED KINASES IN THE RESPONSE TO DNA DAMAGE BY UV

候选人是医学博士。于一九九七年六月完成皮肤科临床训练。他现在正在从事基础研究，目标是成为一名独立研究者。这项研究是在哈佛大学化学和化学生物系的Stuart Schreiber博士的赞助下进行的。Schreiber小组主要关注使用遗传和生化方法来理解和控制细胞周期。太阳紫外线（UV）辐射造成的DNA损伤是皮肤癌的主要原因，皮肤癌是美国最常见的癌症类型。细胞的“紫外线反应”包括激活p53肿瘤抑制蛋白，以保护基因组免受太阳的威胁。完整的反应导致细胞周期阻滞，并允许DNA在复制之前得到修复，防止突变的永久合并。大约90%的鳞状细胞癌缺乏这种紫外线反应，这表明该途径在保护基因组免受紫外线致癌方面具有重要功能。尽管这种保护途径很重要，但目前尚不清楚紫外线对DNA的损伤是如何导致p53诱导的。一种名为ATR的基因已经在Schreiber组中克隆出来，根据初步数据，它很可能是UV-p53反应的中介。ATR属于一个新发现的蛋白质家族，称为pik相关激酶（磷脂酰肌醇激酶相关激酶），在细胞应激（如DNA损伤）后介导细胞周期阻滞。分子和生化方法将用于测试ATR或另一种pik相关激酶是紫外线反应所必需的假设。在诱导或逆转录病毒系统中，显性负ATR等位基因表达会抑制内源性ATR功能。ATR的作用将在对UV-DNA损伤的反应的各个方面进行研究。后续的研究将集中在该途径中的其他蛋白质，包括紫外线反应蛋白的推定底物。该项目将更新和扩展候选人的分子和细胞生物学经验，并在细胞周期调控领域进行培训，为其未来在癌症生物学领域的独立工作提供帮助。从科学上讲，它旨在深入了解紫外线致癌作用，并可能为预防和治疗皮肤癌和更普遍的癌症提供方法。

The candidate is an M.D./Ph.D. who completed clinical training in dermatology in June 1997. He is now pursuing basic research with the goal of a career as an independent investigator. The research is being carried out under the sponsorship of Dr. Stuart Schreiber in the Department of Chemistry and Chemical Biology at Harvard University. The Schreiber group has a major focus on understanding and controlling the cell cycle using genetic and biochemical approaches. DNA damage by solar ultraviolet (UV) radiation is the major cause of skin cancer, the most common type of cancer in the US. A cellular "UV response" involving activation of the p53 tumor suppressor protein has evolved to protect the genome against this solar threat. An intact response leads to cell cycle arrest and allows DNA to be repaired prior to replication preventing the permanent incorporation of mutations. Roughly 90% of squamous cell carcinomas cell carcinomas lack this UV response indicating the essential function of the pathway in protecting the genome from UV carcinogenesis. Despite the importance of this protective pathway, it is not known how DNA damage by UV leads to p53 induction. A gene called ATR has been cloned in the Schreiber group and appears likely to be the mediator of the UV-p53 response based on preliminary data. ATR belongs to a newly described family of proteins called the PIK-related kinases (phosphatidyl inositol kinase-related kinases), which mediate cell cycle arrest after cellular stresses such as DNA damage. Molecular and biochemical approaches will be used to test the hypotheses that ATR or another PIK-related kinase is required for the UV response. Endogenous ATR function will be inhibited with a dominant negative ATR allele expressed in an inducible or retroviral system. The role of ATR will then be examined in individual aspects of the response to UV-DNA damage. Later studies will focus on other proteins in this pathway including putative substrates for the UV-responsive protein. This project will update and expand the candidate's molecular and cellular biology experience and train him in the field of cell cycle regulation, facilitating future independent work in cancer biology. Scientifically it aims to provide insight into UV carcinogenesis and may suggest approaches for the prevention and treatment of skin cancer and cancer more generally.