Understanding and Targeting the DNA Repair Network in Cancer

了解和靶向癌症中的 DNA 修复网络

基本信息

批准号：
8303240
负责人：
Guang Peng
金额：
$ 8.53万
依托单位：
UNIVERSITY OF TX MD ANDERSON CAN CTR
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-07-18 至 2013-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8303240
关键词：
BRCA1 gene BRCA2 gene Binding Biochemical Caenorhabditis elegans Cell Nucleus Cells Characteristics Chromosome Segregation Complex Core Protein Cytoplasm DNA Damage DNA Double Strand Break DNA Repair DNA lesion DNA repair protein Data Defense Mechanisms Development Diagnosis Double Strand Break Repair Drosophila genus Ensure Etiology Foundations Functional disorder Gene Silencing Genetic Genome Genomic Instability Genomics Genotoxic Stress Goals Heterochromatin Human Knowledge Lead Lesion Light Maintenance Malignant Neoplasms Mediating Messenger RNA MicroRNAs Molecular Mutation Nuclear Organism Pathway interactions Phosphorylation Phosphotransferases Play Post-Translational Protein Processing Predisposition Process Proteins Proteomics Publishing RNA RNA Interference Pathway Recruitment Activity Research Role Site Small Interfering RNA Small RNA Stimulus Testing Translating Translational Repression base cancer cell cancer prevention cancer risk career chromatin remodeling clinical application homologous recombination improved inhibitor/antagonist insight novel novel strategies plant fungi prevent programs protein protein interaction recombinational repair repaired response translational study transmission process tumor tumorigenesis

项目摘要

DESCRIPTION (provided by applicant): Genomic instability is a characteristic of cancer cells. Homologous recombination (HR)-mediated DNA repair represents an error-free repairing mechanism to maintain genomic integrity and ensure high-fidelity transmission of genetic information. My long-term goal is to establish a successful and sustainable independent research program with a core competency in the study of HR repair using genomic and proteomic approaches. In my independent career, I wish to pursue (1) fundamental studies to understand HR-mediated DNA repair and its dysfunction in tumorigenesis and (2) mechanism-based translational studies to translate fundamental breakthroughs in HR repair into clinical applications in cancer prevention, diagnosis, prognostication, and therapy. The overall objective of my proposed research, which will lay the foundation for my independent research career, is to understand the novel nuclear function of human Ago2, a core protein in RNA interference pathways, in HR repair and genome maintenance. Based on my preliminary data, I hypothesize that in the context of DNA damage response, via fine-tuned regulatory mechanisms by posttranslational modifications, potentially through ATM/ATR kinase-dependent phosphorylation, human nuclear Ago2 regulates HR repair of double-strand breaks by recruiting DNA repair proteins at damage sites via protein-protein interactions. I will test this hypothesis by pursuing 3 specific aims through an integrated platform that combines mechanistic and functional studies: (1) Determine the function of Ago2 as a novel regulator in HR repair. (2) Characterize posttranslational modifications of Ago2 induced by DNA damage in HR repair. (3) Determine the nuclear function of Ago2 in preventing genomic instability and tumorigenesis. The proposed research is significant because it challenges the current research paradigm that human Ago2 functions predominantly in the cytoplasm. This study will shed light on how 2 evolutionarily conserved genome defense mechanisms, the small regulatory RNA pathways and DNA damage response pathway, converge at DNA lesions in the process of HR repair via the functional involvement of Ago2 protein.

描述（由申请人提供）：基因组不稳定性是癌细胞的一个特征。同源重组 (HR) 介导的 DNA 修复代表了一种无错误的修复机制，可维持基因组完整性并确保遗传信息的高保真度传输。我的长期目标是建立一个成功且可持续的独立研究项目，并在使用基因组和蛋白质组学方法研究 HR 修复方面具有核心能力。在我的独立职业生涯中，我希望从事（1）基础研究，以了解 HR 介导的 DNA 修复及其在肿瘤发生中的功能障碍，以及（2）基于机制的转化研究，将 HR 修复的基本突破转化为癌症预防、诊断的临床应用、预测和治疗。我提出的研究的总体目标是了解人类 Ago2 的新核功能，Ago2 是 RNA 干扰途径、HR 修复和基因组维护中的核心蛋白，这将为我的独立研究生涯奠定基础。根据我的初步数据，我假设在 DNA 损伤反应的背景下，通过翻译后修饰的微调调节机制，可能通过 ATM/ATR 激酶依赖性磷酸化，人核 Ago2 通过招募来调节双链断裂的 HR 修复DNA 通过蛋白质-蛋白质相互作用修复损伤位点的蛋白质。我将通过一个结合机制和功能研究的综合平台追求 3 个具体目标来检验这一假设：(1) 确定 Ago2 作为 HR 修复中的新型调节剂的功能。 (2) 表征 HR 修复中 DNA 损伤诱导的 Ago2 翻译后修饰。 (3)确定Ago2在预防基因组不稳定和肿瘤发生中的核功能。这项研究意义重大，因为它挑战了当前人类 Ago2 主要在细胞质中发挥作用的研究范式。这项研究将揭示两种进化上保守的基因组防御机制，即小调节RNA途径和DNA损伤反应途径，如何通过Ago2蛋白的功能参与在HR修复过程中在DNA损伤处汇聚。