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Identification of a new strategy for cancer therapy

确定癌症治疗新策略

基本信息

批准号：
9305769
负责人：
Hui-Kuan Lin
金额：
$ 35.46万
依托单位：
WAKE FOREST UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-03-09 至 2020-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9305769
关键词：
ATM activation Address Apoptosis BRCA1 Mutation BRCA1 gene BRCA2 Mutation BRCA2 gene Cells Clinical Complex DNA Damage DNA Repair Defect Genetic Genomic Instability Genotoxic Stress Goals Human Light Link Malignant Neoplasms Malignant neoplasm of ovary Mediating Modeling Molecular Mus NBS1 gene Oncogenic Pathway interactions Pharmacology Phosphotransferases Play Recruitment Activity Regulation Role Signal Transduction Sum Telomere Maintenance Telomere Shortening Time Ubiquitin Ubiquitination cancer cell cancer therapy cancer type homologous recombination in vivo inhibitor/antagonist innovation insight killings malignant breast neoplasm multicatalytic endopeptidase complex novel novel strategies novel therapeutics pre-clinical protein complex public health relevance recombinational repair response telomere therapeutic target tumor tumorigenesis ubiquitin-protein ligase

项目摘要

DESCRIPTION (provided by applicant): PARP-1 inhibitors are recently developed and used to target cancers with a defect in homologous recombination (HR) repair, such as BRCA1 or BRCA2 mutations. However, the usage of the PARP inhibitors is profoundly limited by the fact that BRCA1 or BRCA2 mutations only occur in low percentages of human cancers. Thus, identifying critical regulators that control the HR repair is of significance in further understandng DNA damage response and may provide an important therapeutic target for cancer treatments. In this proposal, we set our goals to identify novel regulators in the HR repair pathway that can serve as druggable targets and be used as potential targets in combination with PARP inhibitor to trigger synthetic lethality in cancers. Our study provides the convincing evidence that Skp2 E3 ligase is a novel regulator critical for ATM activation and HR repair, revealing an insight into how DNA damage response is regulated and further providing a new paradigm for a synthetic lethal strategy for cancers. The objectives of this proposal are to determine how Skp2 is recruited to DNA damage foci to regulate ATM activation, how Skp2-medaited NBS1 ubiquitination regulates HR repair and to identify a novel therapeutic strategy for cancer treatment. We will pursue our goals by performing the following specific aims. Aim 1) Understanding the novel regulation of Skp2 E3 ligase in HR repair and genomic instability. Aim 2) To determine the role of K63-linked ubiquitination in the component of the MRN complex in telomere maintenance and DNA damage repair. Aim 3. Understanding novel mechanisms by which Skp2 regulates kinase signaling and tumorigenesis for cancer therapy. In sum, our study provides molecular insights into how MRN complex regulates ATM activation. We show that Skp2 E3 ligase is a critical regulator required for the recruitment of ATM to DNA damage foci and subsequent ATM activation. So far, all Skp2 substrates identified in the last decade are known to undergo ubiquitin- dependent proteasome degradation. However, in this study we identify for the first time a novel non-proteolytic function for Skp2 in DNA damage response. Skp2 triggers non-proteolytic K63-linked ubiquitination of NBS1 and facilitates activation and recruitment of ATM to DNA damage foci. Moreover, we have developed for the first time specific Skp2 inhibitors that can be used for cancer targeting. Our study provides convincing evidence that Skp2 E3 ligase is a novel regulator critical for ATM activation and HR repair, shedding new lights on how DNA damage response is regulated and further offering a new paradigm for a synthetic lethal strategy for cancer treatments.