UFM1 signaling in DNA damage response and cancer therapy

DNA 损伤反应和癌症治疗中的 UFM1 信号传导

• 批准号: 10057359
• 负责人: Zhenkun Lou
• 金额: $ 36.37万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-12-01 至 2022-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10057359
• 关键词: ATM Signaling Pathway; ATM activation; Affect; BRCA1 Mutation; BRCA1 gene; BRCA2 Mutation; Cell Cycle; Cell physiology; Cells; Cleaved cell; Complex; Consensus; DNA Damage; DNA Repair; DNA lesion; Data; Defect; Down-Regulation; Enzymes; Failure; Genome; Genome Stability; Genomic Instability; Hereditary Breast Carcinoma; Histone H4; Human Genetics; Individual; Link; Malignant Neoplasms; Malignant neoplasm of prostate; Modeling; Mutation; NBS1 gene; Pathogenesis; Pathway interactions; Phosphorylation Site; Prostate Cancer therapy; Proteins; Radiation; Radiation Tolerance; Regulation; Resistance; Role; Signal Transduction; Syndrome; System; Testing; Time; Ubiquitin; Ubiquitin Like Proteins; base; cancer cell; cancer predisposition; cancer therapy; chemoradiation; clinically relevant; design; individualized medicine; inhibitor/antagonist; insight; mutant; novel; novel therapeutic intervention; overexpression; prevent; prostate cancer cell; radiation carcinogen; repaired; response; targeted treatment; tumor; tumorigenesis; ubiquitin-protein ligase

To maintain genomic stability, cells have developed an elaborate DNA damage response (DDR) system, which is responsible for sensing DNA damage, halting the ongoing cell cycle, and repairing DNA damage. Failure to detect and repair DNA damage leads to genomic instability, which in turn can drive tumorigenesis. Many human genetic cancer predisposition syndromes are linked to defective DDR. For example, mutations in the BRCA1 gene were found in about 50% of familial breast cancer cases. Because individual tumors often have unique defects in the DDR pathway, insight into the basic mechanisms by which cells repair different DNA lesions could also guide individualized therapy. A promising example is the use of PARP inhibitors in cancers with BRCA1 and BRCA2 mutations. On the other hand, many studies suggest that overexpression of DNA repair factors contributes to resistance to radiochemotherapy. Therefore, studying this pathway has important implications in cancer pathogenesis and cancer therapy. UFM1 is the most recently identified Ub-like proteins. The cellular function of ufmylation remains unclear. Here we show for the first time that Ufm1 signaling is involved in the DNA damage response. We found that the E3 ligase UFL1 is important for ATM activation and Ufl1 deficiency sensitizes prostate cancer cells to radiation. In addition, UfSP2, which cleaves Ufm1 from target proteins, inhibits ATM activation and its overexpression sensitizes cells to DNA damage. Based on these Preliminary Data, we hypothesize that UFL1 and UfSP2 are two new factors in the DNA damage response. UFL1 promotes ATM activation and DDR, while UfSP2 has a opposite function. Because UFL1 and UFM1 are deleted in 20% of prostate cancer, we further hypothesize that defective UFM1 signaling would sensitize prostate cancer to radiation. In this application, we will further explore how UFL1 and UfSP2 regulates NBS1, ATM activation and DDR. In addition, we will examine how UFL1 and UfSP2 themselves are regulated. We will also test the role of UFL1 and UfSP2 in radiosensitivity using clinically relevant models. Our Specific Aims are: Aim 1. Investigate the regulation of ATM signaling by Ufmylation; Aim 2. Study the regulation of UFL1 and UfSP2 by DNA damage signaling; Aim 3. Investigate the role of UFM1 signaling in prostate cancer therapy. Our studies will comprehensively reveal a novel function of UFL1 signaling in the DNA damage response and radiosensitivity. In addition, it will reveal a new therapeutic strategy based on synthetic lethality in treating prostate cancer cells, especially those with deletion of UFL1 or UFM1. !

为了保持基因组的稳定性，细胞已经发展出一种复杂的dna损伤反应(Ddr)。 系统，负责感知DNA损伤，停止正在进行的细胞周期，并修复DNA 损坏。未能检测和修复DNA损伤会导致基因组不稳定，而基因组不稳定又会导致 肿瘤发生学。许多人类遗传性癌症易感综合征与DDR缺陷有关。为 例如，在大约50%的家族性乳腺癌病例中发现了BRCA1基因的突变。因为 个别肿瘤通常在DDR途径中有独特的缺陷，洞察其基本机制 细胞修复不同的DNA损伤也可以指导个体化治疗。一个有希望的例子是使用 BRCA1和BRCA2突变癌症中的PARP抑制剂。另一方面，许多研究表明 DNA修复因子的过度表达导致了对放化疗的抵抗。因此，研究这一点 通路在肿瘤发病机制和肿瘤治疗中具有重要意义。UFM1是最新的 鉴定出类Ub蛋白。超甲基化的细胞功能尚不清楚。这是我们第一次展示 Ufm1信号参与DNA损伤反应的时间。我们发现E3连接酶UFl1是 重要的是ATM激活和Ufl1缺乏使前列腺癌细胞对辐射敏感。此外, 从靶蛋白中切割Ufm1的UfSP2抑制ATM激活，其过度表达使细胞变得敏感 造成DNA损伤。根据这些初步数据，我们推测Ufl1和UfSP2是两个新的 DNA损伤反应中的因素。UFl1促进ATM激活和DDR，而UfSP2有一个 相反的功能。由于UFl1和UFM1在20%的前列腺癌中缺失，我们进一步假设 UFM1信号的缺陷会使前列腺癌对辐射敏感。在此应用程序中，我们将 进一步探讨UFl1和UfSP2如何调控NBS1、ATM激活和DDR。此外，我们还将审查 UFl1和UfSP2本身是如何被调控的。我们还将测试UFl1和UfSP2在 使用临床相关模型的放射敏感性。我们的具体目标是：目标1.调查监管 目的2.研究DNA损伤对UFl1和UfSP2的调控 目的3.研究UFM1信号在前列腺癌治疗中的作用。我们的研究将 全面揭示了UFl1信号在DNA损伤反应和辐射敏感性中的新功能。 此外，它还将揭示一种基于合成致命性的治疗前列腺癌细胞的新策略， 尤其是UFl1或UFM1缺失的患者。 好了！