Mechanisms of Nonhomologous Repair of Damaged DNA

描述(申请人提供)：修复由各种致突变化学物质、辐射和环境制剂造成的DNA损伤是细胞生存的基础。DNA修复失败往往会导致遗传不稳定。DNA双链断裂(DSB)是DNA损伤中最致命的形式之一。因此，所有真核生物都有多种机制来处理DSB。几种人类疾病的存在突显了了解真核DSB修复途径的重要性，这些疾病的特点是免疫功能障碍和受影响的个体对癌症的易感性。这些疾病是DNA修复基因突变的后果。我们实验室的长期目标是确定遗传不稳定性和DSB修复缺陷之间的这种偶然联系。为了实现这一目标，我们需要了解DSB修复的详细分子机制。这项建议将在一个遗传易处理的酵母模型系统中识别和表征非同源末端连接(NHEJ)所涉及的遗传成分，NHEJ是所有真核生物中主要的DSB修复途径。NHEJ组分之间的物理和遗传相互作用的阐明将通过遗传和生化方法的组合实现。总而言之，我们的研究应该会产生涵盖这一关键DNA修复过程的分子机制的机制信息。此外，由于NHEJ的DSB修复在从酵母到人类的过程中非常保守，这些研究将有助于在人类中剖析类似的途径。

DESCRIPTION (provided by applicant): Repair of DNA damage caused by various mutagenic chemicals, radiation, and the environmental agents is fundamental to a cell's survival. Failure of DNA repair often results in genetic instability. DNA double strand break (DSB) is one of the most lethal forms of DNA damage. All eukaryotes thus have multiple mechanisms to deal with DSBs. The importance of understanding eukaryotic DSB repair pathways is highlighted by the existence of several human diseases that are marked by immune dysfunction and predisposition of the affected individuals to cancer. These diseases are the consequences of mutations in DNA repair genes. The long-term goal of our laboratory is to define this casual linkage between the genetic instability and DSB repair defect. To accomplish this goal, we need to understand the detailed molecular mechanisms of DSB repair. This proposal will identify and characterize the genetic components involved in non-homologous end joining (NHEJ), major DSB repair pathway in all eukaryotes, in a genetically tractable yeast model system. Elucidation of the physical and genetic interactions among NHEJ components will be achieved by a combination of genetic and biochemical approaches. Together, our studies should yield the mechanistic information covering the molecular mechanisms of this critical DNA repair process. Furthermore, since DSB repair by NHEJ is remarkably conserved from yeast to humans, these studies will help to dissect the similar pathways in humans.