权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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：
10304188
负责人：
Zhenkun Lou
金额：
$ 35.64万
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 2023-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10304188
关键词：
ATM Signaling Pathway ATM activation Affect BRCA1 Mutation BRCA1 gene BRCA2 Mutation Cell Cycle Cell physiology Cells 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 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 损害未能检测和修复DNA损伤会导致基因组不稳定，这反过来又会导致肿瘤发生许多人类遗传性癌症易感综合征与DDR缺陷有关。为例如，BRCA 1基因的突变在大约50%的家族性乳腺癌病例中被发现。因为个体肿瘤通常在DDR途径中具有独特的缺陷，深入了解其基本机制，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 PARP抑制剂用于BRCA 1和BRCA 2突变的癌症。另一方面，许多研究表明， DNA修复因子的过度表达有助于对放射化学疗法的抗性。因此，研究这个信号通路在癌症发病机制和癌症治疗中具有重要意义。UFM 1是最新的确定了Ub样蛋白。ufmylation的细胞功能仍不清楚。在这里，我们展示了第一个 Ufm 1信号参与DNA损伤反应的时间。我们发现E3连接酶UFL 1是对ATM激活和Ufl 1缺陷很重要，使前列腺癌细胞对辐射敏感。此外，本发明还提供了一种方法， UfSP 2从靶蛋白上切割Ufm 1，抑制ATM活化，其过表达使细胞致敏 DNA损伤。基于这些初步数据，我们假设UFL 1和UfSP 2是两个新的 DNA损伤反应的因素。UFL 1促进ATM激活和DDR，而UfSP 2具有相反的功能。由于UFL 1和UFM 1在20%的前列腺癌中缺失，我们进一步假设缺陷的UFM 1信号会使前列腺癌对辐射敏感。在这个应用程序中，我们将进一步探索UFL 1和UfSP 2如何调节NBS 1，ATM激活和DDR。此外，我们将研究 UFL 1和UfSP 2本身是如何调节的。我们还将测试UFL 1和UfSP 2在放射敏感性使用临床相关模型。我们的具体目标是：目标1。调查对通过Ufmylation的ATM信号传导; Aim 2. DNA损伤对UFL 1和UfSP 2表达调控的研究信号;目标3.研究UFM 1信号在前列腺癌治疗中的作用。我们的研究将全面揭示了UFL 1信号在DNA损伤反应和辐射敏感性中的新功能。此外，它还将揭示一种新的治疗策略，该策略基于治疗前列腺癌细胞的合成致死性，尤其是UFL 1或UFM 1缺失的那些。 !