PIK RELATED KINASES IN THE RESPONSE TO DNA DAMAGE BY UV

该候选人是医学博士/博士，于1997年6月完成皮肤科临床培训。他现在从事基础研究，目标是成为一名独立调查员。这项研究是在哈佛大学化学和化学生物学系的斯图尔特·施赖伯博士的赞助下进行的。Schreiber团队主要致力于使用遗传和生化方法了解和控制细胞周期。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。一种涉及激活P53肿瘤抑制蛋白的细胞“紫外线反应”已经进化出来，以保护基因组免受这种太阳威胁。完整的反应会导致细胞周期停滞，并允许DNA在复制之前得到修复，防止永久结合突变。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。尽管这一保护途径很重要，但紫外线对DNA的损伤如何导致P53的诱导尚不清楚。Schreiber团队已经克隆了一种名为ATR的基因，根据初步数据，该基因似乎可能是UV-P53反应的中介。ATR属于一个新描述的蛋白质家族，称为PIK相关蛋白(磷脂酰肌醇蛋白激酶相关蛋白)，在细胞应激(如DNA损伤)后介导细胞周期停滞。分子和生化方法将被用来检验紫外线反应需要ATR或另一种PIK相关的激酶的假设。内源性ATR功能将被抑制，因为在可诱导或逆转录病毒系统中表达的显性负ATR等位基因。然后，我们将研究ATR在UV-DNA损伤反应的各个方面的作用。以后的研究将集中在这一途径中的其他蛋白质上，包括紫外线反应蛋白的假定底物。该项目将更新和扩展候选人的分子和细胞生物学经验，并在细胞周期调节领域对他进行培训，促进未来在癌症生物学方面的独立工作。从科学上讲，它旨在为紫外线致癌提供洞察力，并可能为皮肤癌和癌症的预防和治疗提供更广泛的建议。

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.