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

基本信息

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
项目类别：
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

项目摘要

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. !

为了维持基因组稳定性，细胞已经形成了精致的DNA损伤反应（DDR）系统，负责感测DNA损伤，停止正在进行的细胞周期并修复DNA 损害。未能检测和修复DNA损伤会导致基因组不稳定性，进而可以驱动肿瘤发生。许多人遗传癌易感综合征与DDR有缺陷有关。为了例如，在大约50％的家族性乳腺癌病例中发现了BRCA1基因中的突变。因为单个肿瘤在DDR途径中通常具有独特的缺陷，深入了解基本机制细胞修复不同的DNA病变也可以指导个性化治疗。一个有希望的例子是使用 BRCA1和BRCA2突变的癌症中的PARP抑制剂。另一方面，许多研究表明 DNA修复因子的过表达有助于对放射化学疗法的抗性。因此，研究这个途径对癌症发病机理和癌症治疗具有重要意义。 UFM1是最近鉴定出UB样蛋白。 ufmylation的细胞功能尚不清楚。我们在这里展示第一个 DNA损伤响应涉及UFM1信号传导的时间。我们发现E3连接酶UFL1是对于ATM激活和UFL1缺乏症至关重要，使前列腺癌细胞敏感到辐射。此外， UFSP2从靶蛋白上切割UFM1，抑制ATM激活，其过表达使细胞敏感进行DNA损伤。基于这些初步数据，我们假设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具有相反的功能。由于UFL1和UFM1在20％的前列腺癌中删除，因此我们进一步假设 UFM1信号有缺陷将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如何调节NBS1，ATM激活和DDR。此外，我们将检查 UFL1和UFSP2本身如何受到调节。我们还将测试UFL1和UFSP2在使用临床相关模型的放射敏性。我们的具体目的是：目标1。调查监管 ufmylation通过ATM信号传导； AIM 2。通过DNA损伤研究UFL1和UFSP2的调节信号传导；目标3。研究UFM1信号传导在前列腺癌治疗中的作用。我们的研究将全面揭示了UFL1信号传导在DNA损伤响应和放射敏感性中的新功能。此外，它将揭示一种基于合成致死性的新治疗策略，用于治疗前列腺癌细胞，特别是那些删除UFL1或UFM1的人。呢