Role of RPA Hyperphosphorylation in DNA Damage Responses

RPA 过度磷酸化在 DNA 损伤反应中的作用

• 批准号: 8291307
• 负责人: Moises Alejandro Serrano
• 金额: $ 3.15万
• 依托单位: EAST TENNESSEE STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-01 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8291307
• 关键词: Address; Binding; Binding Proteins; Biochemical; Biological; Cell Cycle Progression; Cells; Chemicals; Coupling; DNA; DNA Damage; DNA Repair; DNA Repair Pathway; DNA damage checkpoint; DNA lesion; Data; Disease; Double Strand Break Repair; Down-Regulation; Environmental Hazards; Eukaryota; Excision; Exposure to; Failure; Fellowship; Genetic Recombination; Goals; Health; Human; Individual; Instruction; Laboratories; Malignant Neoplasms; Mediating; Metabolic Pathway; Molecular; Mutagenesis; Mutagens; Mutation; National Research Service Awards; Nerve Degeneration; Pathway interactions; Phosphotransferases; Play; Premature aging syndrome; Proteins; Regulation; Replication Initiation; Replication Origin; Role; SS DNA BP; Signal Transduction; Single-Stranded DNA; Source; System; Testing; Time; Work; base; homologous recombination; human disease; insight; origin recognition complex; prevent; repaired; replication factor A; response; success; ultraviolet irradiation

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.

空间 假如。 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，也是许多其他疾病的原因 疾病，如过早衰老和神经退行性疾病。 DNA 修复和 DNA 损伤检查点是 细胞内针对 DNA 损伤的两个主要生物防御系统。两者之间的协调 机器对于及时去除 DNA 损伤、防止 DNA 损伤转化为至关重要 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 很大程度上不为人知。作为真核生物中主要的单链 DNA (ssDNA) 结合蛋白，复制 Protein A (RPA) 参与几乎所有 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都具有关键活性 RPA 是否以及如何在 DNA 修复和 DNA 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。我们实验室的最新研究结果表明，RPA 经历了 DNA 损伤引起的过度磷酸化。在这个项目中，我们将测试以下假设： 过度磷酸化可能会改变 RPA 与 ssDNA 和蛋白质相互作用的生化活性，并且 因此可能构成一些DNA损伤反应相互作用的重要调节机制 由于与分子相互作用的失败或成功，其他的被抑制，而另一些则被激活。 机器人流程自动化。为了检验这些假设，我们将具体确定：1）过度磷酸化的 RPA 在 抑制原点发射； 2）Rad51/Rad52与RPA之间的相互作用以及RPA对其的影响 过度磷酸化； 3) 细胞分子间相互作用的刺激和/或破坏 RPA 过度磷酸化。该项目的长期目标是阐明其分子机制 人类细胞中的 DNA 损伤反应，并更好地了解损伤诱导的突变和 相关人类疾病。 PHS 416-1（修订版 9/08）第 2 页 在整个表格第 2 页的底部连续编号页码 该应用程序。请勿使用 2a、2b 等后缀。 Kirschstein-NRSA 个人奖学金申请 申请人姓名（姓氏、名字、中间名首字母） 莫伊塞斯·塞拉诺 （由申请人填写 - 请遵循 PHS 416-1 说明） 18.