Translesion Synthesis Opposite Carcinogen Bound DNA

跨损伤合成相反致癌物结合 DNA

• 批准号: 7154445
• 负责人: ROBERT L EOFF
• 金额: $ 4.6万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-08-01 至 2009-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7154445
• 关键词: DNA; DNA damage; DNA directed DNA polymerase; carcinogens; enzymes; family; gene mutation; model

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.

描述（由申请人提供）：我们的身体每天都受到一系列潜在的破坏性物质的影响。其中一些代理人来自我们周围的环境，一些是在我们的生活行为中产生的。幸运的是，对于我们的长寿来说，我们的细胞内已经进化出了修复我们所经历的大部分损伤的系统。防止我们遗传密码永久性损伤的最后一道防线之一存在于一类称为Y家族聚合酶的酶中。这些分子马达在处理受损DNA的能力上是独一无二的。然而，考虑到DNA损伤类型的真实丛林，关于Y家族聚合酶如何修复损伤，我们还不了解许多事情。为了解决关于Y家族聚合酶绕过受损DNA的无数未回答的问题，该提案将研究一种称为Dpo 4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DNA损伤形式是由于暴露于不仅在环境中发现而且还用于化疗方案以治疗多种类型的癌症的药剂而导致的。动力学分析将与X射线晶体学研究相结合，以便将结构与功能结合起来。