RAD51 paralog function in cancer predisposition and genome integrity

RAD51 旁系同源物在癌症易感性和基因组完整性中的功能

基本信息

批准号：
10745028
负责人：
Kara A Bernstein
金额：
$ 46.12万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-12-01 至 2026-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10745028
关键词：
ATP phosphohydrolase Address Aging BRCA2 gene Biochemical Biological Biological Assay Biological Markers Bleomycin Cells Chromosome abnormality Classification Clinical Clustered Regularly Interspaced Short Palindromic Repeats Co-Immunoprecipitations Complex DNA Damage DNA Double Strand Break DNA Repair DNA Repair Pathway DNA replication fork DNA-Protein Interaction Development Double Strand Break Repair Embryo Environment Environmental Carcinogens Environmental Exposure Exposure to Filament Functional disorder Genetic Genetic Polymorphism Genetic Screening Genomic Instability Germ-Line Mutation Goals Hereditary Breast and Ovarian Cancer Syndrome Human Human Cell Line Hybrids Individual Inflammatory Response Inherited Injury Invaded Ionizing radiation Knock-in Knock-out Knockout Mice Knowledge Link Malignant Neoplasms Malignant neoplasm of ovary Mammary Neoplasms Measures Mediating Metaphase Methods Microscopy Modeling Molecular Mus Mutate Mutation Oxidative Stress Induction PALB2 gene Pathogenicity Pathway interactions Proteins RAD51C gene Recombinant Proteins Reporter Role Screening for Ovarian Cancer Source System Technology Testing Therapeutic Time Toxic Environmental Substances Tracer Variant Visualization Walker-A Motif Woman Work XRCC2 gene XRCC3 gene Yeasts brca gene cancer genome cancer predisposition cancer risk cost effective environmental mutagens epidemiology study experimental study gene repair genome integrity high throughput screening homologous recombination in vivo individual patient malignant breast neoplasm member mutant next generation sequencing novel ovarian neoplasm oxidative damage paralogous gene precision medicine prevent protein protein interaction recruit repaired screening panel toxicant tumor variant of unknown significance

项目摘要

Project Summary/Abstract: Accurate repair of DNA damage is critical for genetic stability, and for preventing aging-related degeneration and cancer. We are working to identify key factors that regulate accurate repair of DNA double-strand breaks (DSBs) through the error-free homologous recombination (HR) pathway. DSBs can arise from many sources including endogenous replication fork damage, exogenous environmental toxicants, or oxidative stresses induced by endogenous sources and during pro-inflammatory responses to toxicant injury. We found that the RAD51 paralogs are critical for promoting HR and hence for suppressing error-prone repair mechanisms. Over 300 studies link mutations in human RAD51 paralogs with cancer, and women with breast or ovarian cancer are now screened for RAD51 paralog mutations. However, it remains largely unknown which RAD51 paralog mutations are pathogenic and how these mutations sensitize individuals to environmentally induced-DNA damage due to our lack of functional analysis of either the wild-type or mutated proteins. We do not know how these proteins are recruited, their functional components, or the disruptions caused by mutations or polymorphisms in the RAD51 paralogs. This knowledge gap results from low abundance of endogenous RAD51 paralog proteins, insolubility of the recombinant proteins, as well as embryonic lethality in knock-out mice. We are therefore using genetic, biochemical, and cell biological approaches to characterize RAD51 paralog function upon exposure to DSB inducing agents. We will use ionizing radiation (IR) and bleomycin as model agents for environmentally relevant DSB-inducing agents. Using complementary approaches in combination with high-throughput genetic screening, we are now uniquely poised to address how RAD51 paralog mutations predispose individuals to human cancer and thus, to identify opportunities for determining who is at risk for cancer development upon exposure to environmental carcinogens. Our ultimate goal is to enable development of precision medicine strategies for individual patients whose tumors harbor a RAD51 paralog mutation profile.

项目摘要/摘要： DNA 损伤的准确修复对于遗传稳定性和预防与衰老相关的退化至关重要和癌症。我们正在努力确定调节 DNA 双链断裂精确修复的关键因素（DSB）通过无错误同源重组（HR）途径。 DSB 的产生有多种来源包括内源性复制叉损伤、外源性环境毒物或氧化应激由内源性来源和对毒物损伤的促炎反应引起。我们发现 RAD51 旁系同源物对于促进 HR 至关重要，从而抑制容易出错的修复机制。超过 300 项研究将人类 RAD51 旁系同源物的突变与癌症以及女性乳腺癌或卵巢癌联系起来现在筛选 RAD51 旁系同源突变。然而，目前尚不清楚 RAD51 旁系同源物是哪个突变是致病性的，以及这些突变如何使个体对环境诱导的 DNA 敏感由于我们缺乏对野生型或突变蛋白的功能分析而造成损害。我们不知道如何这些蛋白质被招募，它们的功能成分，或由突变或引起的破坏 RAD51旁系同源物的多态性。这种知识差距是由于内源性物质丰度低造成的 RAD51旁系同源蛋白、重组蛋白的不溶性以及敲除中的胚胎致死率老鼠。因此，我们使用遗传、生化和细胞生物学方法来表征 RAD51 暴露于 DSB 诱导剂后的旁系同源功能。我们将使用电离辐射 (IR) 和博莱霉素作为环境相关 DSB 诱导剂的模型剂。使用互补的方法与高通量基因筛查相结合，我们现在准备好解决 RAD51 如何旁系同源突变使个体易患人类癌症，因此，确定确定的机会接触环境致癌物后有患癌症风险的人。我们的最终目标是为肿瘤携带 RAD51 的个体患者制定精准医疗策略旁系同源突变谱。