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Novel regulations of DNA damage repair

DNA损伤修复的新调控

基本信息

批准号：
10087898
负责人：
Junjie Chen
金额：
$ 43.64万
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：
2017-03-16 至 2024-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10087898
关键词：
Affinity Chromatography BRCA mutations BRCA1 gene Binding Proteins Cancer Etiology Cancer Patient Cell Death Cell Nucleus Cells Chromatin Clinical Coupled DNA DNA Damage DNA Double Strand Break DNA Repair DNA Repair Gene DNA Repair Pathway DNA damage checkpoint DNA lesion Data Defect Double Strand Break Repair Genes Genome Genomic Instability Goals Human Immunoglobulin Class Switching Immunoglobulin Switch Recombination Knockout Mice Laboratories Lead Maintenance Malignant Neoplasms Malignant neoplasm of ovary Mass Spectrum Analysis Mediating Molecular Mutagenesis Mutation Nonhomologous DNA End Joining Outcome Pathway interactions Play Poly(ADP-ribose) Polymerases Process Proteins Radiation Regulation Resistance Role Signal Pathway Site Source Sun Exposure Tumor Suppressor Proteins base brca gene cancer therapy chemotherapeutic agent driving force genome integrity homologous recombination in vivo inhibitor/antagonist malignant breast neoplasm mutant neoplastic cell novel p53-binding protein 1 patient response recombinational repair recruit repaired resistance mechanism response senescence targeted cancer therapy therapy resistant treatment response tumorigenesis

项目摘要

PROJECT SUMMARY Defects in DNA damage response and DNA repair are the driving forces of genomic instability and tumorigenesis. Gaining a better understanding of the pathways involved in DNA repair not only increases our understanding of cancer etiology, but also provides new targets for cancer therapies. A key protein involved in DNA repair and tumorigenesis is p53-binding protein 1, i.e. 53BP1. My laboratory has been working on 53BP1 for many years. Our group was one of the first to demonstrate the role of 53BP1 in DNA damage response. We established the first 53bp1 knockout (KO) mice; we also 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. We and others demonstrated that the H2AX-dependent DNA damage signaling pathway controls the recruitment and accumulation of 53BP1 at sites of DNA breaks. However, 53BP1 can also localize to DNA damage sites in an H2AX-independent manner, although the underlying mechanisms remain to be determined. Moreover, we showed that 53BP1 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 pathway. Our recent studies and those of others suggest that 53BP1 suppresses homologous recombination repair in BRCA1-deficient cells, which is critically important for response to poly (ADP-ribose) polymerase inhibitor-based cancer therapies. Together, these data highlight the importance of 53BP1 in counteracting homologous recombination repair in response to DNA damage. In this proposal, we plan to focus on 53BP1 and elucidate at the molecular level how 53BP1 is regulated after DNA damage and contributes to DNA repair and genome maintenance. To further understand the regulation of 53BP1 localization and function at DNA damage sites, we recently performed tandem affinity purification coupled with mass spectrometry analysis to identify proteins that would specifically associate with a region of 53BP1, which is necessary and sufficient for its localization to DNA damage sites. Surprisingly, we uncovered several novel 53BP1-binding proteins, including NUDT16, NUDT16L1, and DEK. In this proposal, we will 1) further determine the roles of NUDT16L1 and NUDT16 in 53BP1 regulation and in the DNA damage response, and 2) elucidate the functional significance of DEK and other newly discovered 53BP1-associated proteins in damage-induced 53BP1 localization, DNA repair, and the maintenance of genomic integrity. These studies will help us understand the key components that act upstream of 53BP1 and function together with 53BP1 in DNA repair and genome maintenance.

项目摘要 DNA损伤反应和DNA修复的缺陷是基因组不稳定性的驱动力，肿瘤发生更好地了解DNA修复中涉及的途径不仅可以增加我们的免疫力，这不仅有助于了解癌症病因，而且还为癌症治疗提供了新的靶点。一种关键蛋白质， DNA修复和肿瘤发生是p53结合蛋白1，即53 BP 1。我的实验室多年来一直在研究53 BP 1。我们是第一批证明 53 BP 1在DNA损伤反应中的作用我们建立了第一个53 bp 1敲除（KO）小鼠;我们还揭示了53 BP 1是DNA修复所必需的，并在体内充当肿瘤抑制因子。另外我们阐明了53 BP 1在DNA损伤后的调节作用。我们和其他人证明了H2 AX依赖性 DNA损伤信号通路控制53 BP 1在DNA断裂位点的募集和积累。然而，53 BP 1也可以以不依赖H2 AX的方式定位于DNA损伤位点，尽管53 BP 1的表达与H2 AX无关。根本机制仍有待确定。此外，我们发现53 BP 1对一个特定的这一修复过程被称为类别转换重组，表明53 BP 1参与了一种特殊的DNA修复这是明显不同于典型的非同源末端连接途径的途径。我们最近的研究和其他人的结果表明，53 BP 1抑制BRCA 1缺陷的同源重组修复，细胞，这是至关重要的反应聚（ADP-核糖）聚合酶的癌症为基础的治疗总之，这些数据突出了53 BP 1在抵消同源重组中的重要性修复DNA损伤。在这项提议中，我们计划集中在53 BP 1和阐明在分子水平上，水平53 BP 1是如何在DNA损伤后调节，并有助于DNA修复和基因组维护。为了进一步了解53 BP 1在DNA损伤位点的定位和功能调节，我们最近进行串联亲和纯化，结合质谱分析，以鉴定特异性地与53 BP 1区域相关，该区域对于其定位于DNA是必需和充分的损伤部位。令人惊讶的是，我们发现了几种新的53 BP 1结合蛋白，包括NUDT 16， NUDT 16 L1和DEK.在本提案中，我们将1）进一步确定NUDT 16 L1和NUDT 16在以下方面的作用： 53 BP 1调控和DNA损伤反应，2）阐明DEK和其他新发现的53 BP 1相关蛋白在损伤诱导的53 BP 1定位，DNA修复，保持基因组的完整性。这些研究将帮助我们了解 53 BP 1的上游，并与53 BP 1一起在DNA修复和基因组维护中发挥作用。

项目成果

期刊论文数量（16）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Interactomes of SARS-CoV-2 and human coronaviruses reveal host factors potentially affecting pathogenesis.

DOI：
10.15252/embj.2021107776
发表时间：
2021-09-01
期刊：
The EMBO journal
影响因子：
0
作者：
Chen Z;Wang C;Feng X;Nie L;Tang M;Zhang H;Xiong Y;Swisher SK;Srivastava M;Chen J
通讯作者：
Chen J

Histone chaperone ASF1 acts with RIF1 to promote DNA end joining in BRCA1-deficient cells.

DOI：
10.1016/j.jbc.2022.101979
发表时间：
2022-06
期刊：
JOURNAL OF BIOLOGICAL CHEMISTRY
影响因子：
4.8
作者：
Tang, Mengfan;Chen, Zhen;Wang, Chao;Feng, Xu;Lee, Namsoo;Huang, Min;Zhang, Huimin;Li, Siting;Xiong, Yun;Chen, Junjie
通讯作者：
Chen, Junjie

Biological and clinical aspects of HPV-related cancers.