Identification of a new strategy for cancer therapy

确定癌症治疗新策略

• 批准号: 9031736
• 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
• 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/9031736
• 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; Lead; Light; Link; Malignant Neoplasms; Malignant neoplasm of ovary; Mediating; Modeling; Molecular; Mus; NBS1 gene; Oncogenic; Pathway interactions; 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

 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.

 描述（由申请人提供）：PARP-1抑制剂最近被开发出来并用于靶向同源重组（HR）修复缺陷的癌症，例如BRCA1或BRCA2突变。然而，由于 BRCA1 或 BRCA2 突变仅发生在低比例的人类癌症中，PARP 抑制剂的使用受到严重限制。因此，识别控制 HR 修复的关键调节因子对于进一步了解 DNA 损伤反应具有重要意义，并可能为癌症治疗提供重要的治疗靶点。在这项提案中，我们设定的目标是确定 HR 修复途径中的新型调节剂，这些调节剂可以作为可药物靶点，并可作为与 PARP 抑制剂联合使用的潜在靶点，以触发癌症的合成致死性。我们的研究提供了令人信服的证据，证明 Skp2 E3 连接酶是一种对 ATM 激活和 HR 修复至关重要的新型调节因子，揭示了 DNA损伤反应是如何调节的，并进一步为癌症的合成致死策略提供了新的范例。该提案的目的是确定 Skp2 如何被招募到 DNA 损伤灶来调节 ATM 激活，Skp2 介导的 NBS1 泛素化如何调节 HR 修复，并确定一种新的癌症治疗策略。我们将通过实现以下具体目标来实现我们的目标。目标 1) 了解 Skp2 E3 连接酶在 HR 修复和基因组不稳定性中的新调控。目的 2) 确定 MRN 复合体成分中 K63 连接的泛素化在端粒维持和 DNA 损伤修复中的作用。目标 3. 了解 Skp2 在癌症治疗中调节激酶信号传导和肿瘤发生的新机制。总之，我们的研究提供了 MRN 复合物如何调节 ATM 激活的分子见解。我们证明 Skp2 E3 连接酶是 ATM 募集到 DNA 损伤灶以及随后 ATM 激活所需的关键调节因子。到目前为止，已知过去十年中发现的所有 Skp2 底物都会经历泛素依赖性蛋白酶体降解。然而，在这项研究中，我们首次发现了 Skp2 在 DNA 损伤反应中的一种新的非蛋白水解功能。 Skp2 触发 NBS1 的非蛋白水解 K63 泛素化，并促进 ATM 的激活和招募至 DNA 损伤灶。此外，我们首次开发了可用于癌症靶向的特异性Skp2抑制剂。我们的研究提供了令人信服的证据，证明 Skp2 E3 连接酶是一种对 ATM 激活和 HR 修复至关重要的新型调节剂，为了解 DNA 损伤反应的调节方式提供了新的线索，并进一步为癌症治疗的合成致死策略提供了新的范例。