Role of RPA Hyperphosphorylation in DNA Damage Responses

空间 提供了 环境危害，包括紫外线照射和遗传毒性化学品，是一些主要来源， DNA损伤被认为是人类癌症的主要原因，也是许多其他癌症的原因。 如过早衰老和神经退化等疾病。DNA修复和DNA损伤检查点是 这两个主要的生物防御系统对抗细胞中的DNA损伤。这两者之间的协调 机械对于及时清除DNA损伤，防止DNA损伤转化为 由于复制不忠实而导致的永久性突变。然而，配位的分子细节仍然存在 大部分未知。作为真核生物中主要的单链DNA（ssDNA）结合蛋白， 蛋白A（protein A，RPA）参与几乎所有的DNA代谢途径，如复制、重组、DNA 损伤检查点和所有类型的DNA修复途径。尽管它在所有这些途径中具有重要的活性 RPA是否以及如何在DNA修复和修复之间的精确协调中发挥作用的问题， 检查点仍有待阐明。我们实验室最近的研究结果表明，RPA经历了 对DNA损伤的反应。在这个项目中，我们将测试的假设， 过度磷酸化可以改变RPA与ssDNA和蛋白质相互作用的生物化学活性， 因此可能构成了一种重要的调节机制，通过这种机制，一些DNA损伤反应相互作用 的分子相互作用的失败或成功， RPA。为了验证这些假设，我们将具体确定：1）过度磷酸化RPA在 Rad 51/Rad 52与RPA之间的相互作用及RPA的影响 高磷酸化;和3）细胞分子相互作用刺激和/或破坏的 RPA过度磷酸化。本项目的长期目标是阐明 人类细胞中的DNA损伤反应，并更好地了解损伤诱导的诱变和 相关的人类疾病。 PHS 416-1（修订版9/08）第2页表格第2页底部连续编号 应用程序.不要使用后缀，如2a，2b。 Kirschstein-NRSA个人奖学金申请申请人姓名（姓、名、中间名首字母） 莫伊塞斯？塞拉诺 (To由申请人填写-遵循PHS 416-1指示） 18.

SPACE PROVIDED. Environmental hazards, including UV irradiation and genotoxic chemicals, are some of the major sources for DNA damage and believed to be the major cause to human cancers and also a cause to many other diseases such as premature aging and neurodegeneration. DNA repair and DNA damage checkpoints are the two major biological defense systems against DNA damage in cells. Coordination between these two machineries is crucial for timely removal of DNA damage, preventing the conversion of DNA lesions to permanent mutations due to replication infidelity. However, the molecular details of the coordination remain largely unknown. As the major single-stranded DNA (ssDNA) binding protein in eukaryotes, replication protein A (RPA) is involved in almost all DNA metabolic pathways such as replication, recombination, DNA damage checkpoints, and all types of DNA repair pathways. Despite its critical activity in all these pathways the question of whether and how RPA plays a role in the precise coordination between DNA repair and checkpoints remain to be elucidated. Recent findings from our laboratory have shown that RPA undergoes hyperphosphorylatlon in response to DNA damage. In this project we will test the hypothesis that the hyperphosphorylatlon may alter the biochemical activity of RPA for interaction with ssDNA and proteins, and thus may constitute an important regulatory mechanism by which some DNA damage response interactions are inhibited while others are activated owing to the failure or success of the molecular interactions with RPA. To test these hypotheses, we will specifically determine: 1) the role of hyperphosphorylated RPA in the suppression of origin firing; 2) the interaction between Rad51/Rad52 and RPA and its effect by RPA hyperphosphorylatlon; and 3) the cellular molecular interactions stimulated and/or disrupted by the hyperphosphorylation of RPA. The long-term goal of this project is to elucidate the molecular mechanism of DNA damage responses in human cells, and to better understand the damage-induced mutagenesis and related human diseases. PHS 416-1 (Rev. 9/08) Page 2 Number pages consecutively at the bottom throughout Form Page 2 the application. Do not use suffixes such as 2a, 2b. Kirschstein-NRSA Individual Fellowship Application NAME OF APPLICANT (Last, first, middle initial) Serrano, Moises A (To be completed by applicant - follow PHS 416-1 instructions) 18.