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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：
9883637
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 2022-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9883637
关键词：
Affinity Chromatography 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 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.

项目总结