Translesion Synthesis Opposite Carcinogen Bound DNA

描述(由申请者提供)：我们的身体每天都会受到潜在破坏性物质的攻击。其中一些来自我们周围的环境，另一些则是由我们的生活行为在我们体内产生的。幸运的是，对于我们的长寿来说，细胞内的系统已经进化，修复了我们经历的大部分损伤。防止我们的遗传密码永久受损的最后一道防线之一存在于一种名为Y家族聚合酶的酶中。这些分子马达在处理受损DNA的能力方面是独一无二的。然而，鉴于DNA损伤的种类繁多，关于Y家族聚合酶如何修复损伤，还有许多事情我们还不清楚。为了解决关于Y家族聚合酶绕过受损DNA的无数悬而未决的问题，这项提案将研究名为Dpo4的模型Y家族聚合酶复制过去一种非常常见的DNA损伤形式的能力，这种损伤是由于暴露于不仅在环境中发现的药物，而且也用于化疗方案来治疗多种类型的癌症。动力学分析将与X射线结晶学研究相结合，以便将结构与功能结合起来。

DESCRIPTION (provided by applicant): Our bodies are subjected to a barrage of potentially damaging agents every day. Some of these agents come from the environment surrounding us and some are generated inside us by the very act of living. Fortunately for our longevity, systems have evolved within our cells that repair much of the damage that we experience. One of the last lines of defense against permanent damage to our genetic code resides in a class of enzymes called the Y-family polymerases. These molecular motors are unique in their ability to deal with damaged DNA. However, given the veritable jungle of types of DNA lesions, there are many things that we do not yet understand concerning how the Y-family polymerases repair damage. In an effort to address the myriad of unanswered questions regarding Y-family polymerase bypass of damaged DNA, this proposal will study the ability of a model Y-family polymerase called Dpo4 to copy past a very common form of DNA damage that results from exposure to agents that are not only found in the environment but are also used in chemotherapeutic regimes to treat multiple types of cancer. Kinetic analyses will be combined with x-ray crystallographic studies in order to couple structure with function.