53BP1-dependent pathway in DNA repair

DNA 修复中 53BP1 依赖性途径

基本信息

批准号：
9763542
负责人：
Junjie Chen
金额：
$ 35.5万
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：
2017
资助国家：
美国
起止时间：
2017-06-14 至 2023-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9763542
关键词：
Adaptor Signaling Protein BRCA1 gene Cancer Biology Cancer Patient Cell Line Cell Survival Cells Complex DNA DNA Damage DNA Double Strand Break DNA Repair DNA Repair Pathway DNA damage checkpoint Data Excision Fanconi Anemia pathway Genetic Epistasis Genome Genomic Instability Goals Hypersensitivity Immunoglobulin Class Switching Immunoglobulin Switch Recombination Knock-out Knockout Mice Knowledge Laboratories Libraries Maintenance Mediating Molecular NBS1 gene Nonhomologous DNA End Joining Pathway interactions Play Poly(ADP-ribose) Polymerases Prevention Process Proteins Public Health Regulation Research Resistance Role Series Signal Pathway Site Tumor Suppressor Proteins artemis base cancer therapy homologous recombination improved in vivo inhibitor/antagonist interest novel p53-binding protein 1 prevent recombinational repair recruit repaired response tumorigenesis

项目摘要

PROJECT SUMMARY Despite rapid progress in defining distinct DNA repair pathways over the past few years, our knowledge of p53-binding protein 1 (53BP1) in DNA repair remains incomplete. My laboratory is interested in elucidating the molecular mechanisms underlying genomic instability and tumorigenesis. Since I started my laboratory in 1999, we have discovered and characterized many essential DNA damage checkpoint and repair proteins. Our long-term goal is to reveal the complex regulation of the DNA repair network, which will permit us to meaningfully contribute to cancer biology and treatment. This proposal focuses on 53BP1, a key component in DNA repair. Many years ago, our group was one of the first to demonstrate the role of 53BP1 in DNA damage response. We established the first 53bp1 knockout mice and revealed that 53BP1 is required for DNA repair and acts as a tumor suppressor in vivo. In addition, we elucidated the regulation of 53BP1 after DNA damage. In particular, over the past decade, we and others demonstrated that the H2AX-dependent DNA damage signaling pathway, composed of H2AX, MDC1, RNF8, and RNF168, controls the recruitment and accumulation of 53BP1 at sites of DNA breaks. In particular, we showed that 53BP1, because of its role in DNA repair, is critical for a particular repair process called class- switch recombination, indicating that 53BP1 is involved in a special DNA repair pathway that is distinctly different from the canonical nonhomologous end-joining (NHEJ) pathway. Moreover, our recent studies and those of others suggest that 53BP1 controls two downstream sub-pathways and suppresses homologous recombination (HR) repair in BRCA1-deficient cells, which is critically important for response to cancer therapies based on poly (ADP-ribose) polymerase inhibitors (PARPi). Together, these data highlight the existence of a bona fide 53BP1-dependent repair pathway that has not been thoroughly investigated. Our goals in this proposal are to further understand the 53BP1-dependent repair pathway and reveal mechanistically how it counteracts the HR repair pathway in response to DNA damage. To achieve these goals, we propose the following specific aims: 1) delineate the 53BP1-dependent end- joining repair pathway; 2) elucidate the molecular mechanisms underlying the regulation and function of the RIF1-REV7 branch of the 53BP1-dependent repair pathway; and 3) reveal mechanistically how the HR pathway operates in the absence of BRCA1 and 53BP1. These proposed studies are significant because they not only will elucidate the 53BP1-dependent repair pathway in the complex DNA repair network, but also will provide ways to overcome therapy resistance for cancer patients.

项目概要尽管过去几年在定义不同的 DNA 修复途径方面取得了快速进展，但我们对 DNA 修复中的 p53 结合蛋白 1 (53BP1) 仍然不完整。我的实验室有兴趣阐明基因组不稳定性和肿瘤发生的分子机制。自从我开始我的实验室以来 1999 年，我们发现并表征了许多重要的 DNA 损伤检查点和修复蛋白。我们的长期目标是揭示 DNA 修复网络的复杂调控，这将使我们能够对癌症生物学和治疗做出有意义的贡献。该提案重点关注 DNA 修复的关键成分 53BP1。许多年前，我们小组是其中之一第一个证明 53BP1 在 DNA 损伤反应中的作用。我们建立了第一个 53bp1 敲除小鼠并发现 53BP1 是 DNA 修复所必需的，并在体内充当肿瘤抑制因子。此外，我们阐明了 DNA 损伤后 53BP1 的调节。特别是在过去的十年里，我们和其他人证明 H2AX 依赖性 DNA 损伤信号通路由 H2AX、MDC1、RNF8 组成， RNF168 控制 53BP1 在 DNA 断裂位点的募集和积累。特别是，我们表明 53BP1 由于其在 DNA 修复中的作用，对于称为类的特定修复过程至关重要开关重组，表明 53BP1 参与了一种特殊的 DNA 修复途径，该途径明显与典型的非同源末端连接（NHEJ）途径不同。此外，我们最近的研究和其他人的研究表明 53BP1 控制两个下游子通路并抑制同源 BRCA1 缺陷细胞中的重组 (HR) 修复，这对于癌症反应至关重要基于聚（ADP-核糖）聚合酶抑制剂（PARPi）的疗法。这些数据共同凸显了是否存在真正的 53BP1 依赖性修复途径，但尚未得到彻底研究。我们的该提案的目标是进一步了解 53BP1 依赖性修复途径并揭示从机制上讲，它如何对抗 DNA 损伤时的 HR 修复途径。为了实现这些目标，我们提出以下具体目标：1）描绘53BP1依赖的末端- 加入修复途径； 2）阐明其调控和功能的分子机制 53BP1 依赖性修复途径的 RIF1-REV7 分支； 3）机械地揭示HR如何该途径在 BRCA1 和 53BP1 缺失的情况下发挥作用。这些拟议的研究意义重大，因为它们不仅将阐明复杂DNA修复网络中依赖于53BP1的修复途径，而且还将为癌症患者提供克服治疗耐药性的方法。