Identification of a new strategy for cancer therapy

 描述（由申请人提供）：PARP-1抑制剂是最近开发的，用于靶向同源重组（HR）修复缺陷（如BRCA 1或BRCA 2突变）的癌症。然而，PARP抑制剂的使用受到BRCA 1或BRCA 2突变仅在低百分比的人类癌症中发生的事实的深刻限制。因此，确定控制HR修复的关键调节因子对于进一步理解DNA损伤反应具有重要意义，并且可能为癌症治疗提供重要的治疗靶点。在这项提案中，我们设定了我们的目标，以确定HR修复途径中的新型调节剂，这些调节剂可以作为可药物化的靶点，并作为潜在的靶点与PARP抑制剂联合使用，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，Skp 2 E3连接酶是ATM激活和HR修复的一种新的关键调节剂，揭示了对ATM激活和HR修复的深入了解。 如何调节DNA损伤反应，并进一步为癌症的合成致死策略提供新的范例。该提案的目的是确定Skp 2如何被招募到DNA损伤灶以调节ATM激活，Skp 2介导的NBS 1泛素化如何调节HR修复，并确定癌症治疗的新治疗策略。我们将通过实现以下具体目标来追求我们的目标。目的1）了解Skp 2 E3连接酶在HR修复和基因组不稳定性中的新调控。目的2）探讨MRN复合物中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Skp 2调节激酶信号传导和肿瘤发生的新机制，用于癌症治疗。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。我们表明，Skp 2 E3连接酶是一个关键的调节器所需的招聘ATM的DNA损伤灶和随后的ATM激活。到目前为止，已知在过去十年中鉴定的所有Skp 2底物都经历泛素依赖性蛋白酶体降解。然而，在这项研究中，我们首次确定了一种新的非蛋白水解功能Skp 2的DNA损伤反应。Skp 2触发NBS 1的非蛋白水解K63连接的泛素化，并促进ATM的激活和招募到DNA损伤灶。此外，我们还首次开发了可用于癌症靶向的特异性Skp 2抑制剂。我们的研究提供了令人信服的证据，证明Skp 2 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DNA损伤反应如何调节提供了新的线索，并进一步为癌症治疗的合成致死策略提供了新的范例。

 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.