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. !

为了维持基因组稳定性，细胞产生了复杂的 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，进而导致肿瘤发生。许多人类遗传性癌症易感综合症与 DDR 缺陷有关。为了例如，大约 50% 的家族性乳腺癌病例中发现了 BRCA1 基因突变。因为个体肿瘤往往在 DDR 通路中存在独特的缺陷，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 抑制剂治疗具有 BRCA1 和 BRCA2 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会导致对放化疗的抵抗。因此，研究这个途径在癌症发病机制和癌症治疗中具有重要意义。 UFM1 是最新的鉴定出 Ub 样蛋白。 ufmylation 的细胞功能仍不清楚。这里我们先展示一下 Ufm1 信号传导参与 DNA 损伤反应的时间。我们发现E3连接酶UFL1是对 ATM 激活很重要，Ufl1 缺陷会使前列腺癌细胞对辐射敏感。此外， UfSP2 可将 Ufm1 从靶蛋白上裂解下来，抑制 ATM 激活，其过度表达会使细胞变得敏感对DNA损伤。根据这些初步数据，我们假设 UFL1 和 UfSP2 是两个新的 DNA损伤反应的影响因素。 UFL1 促进 ATM 激活和 DDR，而 UfSP2 则具有相反的功能。由于 20% 的前列腺癌中 UFL1 和 UFM1 被删除，我们进一步假设有缺陷的 UFM1 信号传导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 本身是如何调节的。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. 调查监管通过 Ufmylation 进行 ATM 信号传输；目标2.研究DNA损伤对UFL1和UfSP2的调控信号发送；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 信号在 DNA 损伤反应和放射敏感性中的新功能。此外，它将揭示一种基于治疗前列腺癌细胞的合成致死性的新治疗策略，尤其是那些删除了 UFL1 或 UFM1 的。！

项目成果

期刊论文数量（6）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Ubiquitin and ubiquitin-like molecules in DNA double strand break repair.

DNA 双链断裂修复中的泛素和泛素样分子。

DOI：
发表时间：
2020
期刊：
影响因子：
0
作者：
Yu, Jia;Qin, Bo;Lou, Zhenkun
通讯作者：
Lou, Zhenkun

Dynamic recruitment of UFM1-specific peptidase 2 to the DNA double-strand breaks regulated by WIP1.

UFM1 特异性肽酶 2 动态募集至 WIP1 调节的 DNA 双链断裂处。

DOI：
发表时间：
2022
期刊：
影响因子：
0
作者：
Qin, Bo;Yu, Jia;Zhao, Fei;Huang, Jinzhou;Zhou, Qin;Lou, Zhenkun
通讯作者：
Lou, Zhenkun

UFL1 promotes histone H4 ufmylation and ATM activation.

UFL1 促进组蛋白 H4 ufmylation 和 ATM 激活。

DOI：
发表时间：
2019
期刊：
影响因子：
16.6
作者：
Qin, Bo;Yu, Jia;Nowsheen, Somaira;Wang, Minghui;Tu, Xinyi;Liu, Tongzheng;Li, Honglin;Wang, Liewei;Lou, Zhenkun
通讯作者：
Lou, Zhenkun

STK38 promotes ATM activation by acting as a reader of histone H4 ufmylation.

STK38 通过充当组蛋白 H4 ufmylation 的读取器来促进 ATM 激活。

DOI：
发表时间：
2020
期刊：
影响因子：
13.6
作者：
Qin, Bo;Yu, Jia;Nowsheen, Somaira;Zhao, Fei;Wang, Liewei;Lou, Zhenkun
通讯作者：
Lou, Zhenkun

A novel UCHL3 inhibitor, perifosine, enhances PARP inhibitor cytotoxicity through inhibition of homologous recombination-mediated DNA double strand break repair.

一种新型 UCHL3 抑制剂 perifosine 通过抑制同源重组介导的 DNA 双链断裂修复来增强 PARP 抑制剂的细胞毒性。

DOI：
发表时间：
2019-05-21
期刊：
影响因子：
9
作者：
Song, Zhiwang;Tu, Xinyi;Zhou, Qin;Huang, Jinzhou;Chen, Yuping;Liu, Jiaqi;Lee, SeungBaek;Kim, Wootae;Nowsheen, Somaira;Luo, Kuntian;Yuan, Jian;Lou, Zhenkun
通讯作者：
Lou, Zhenkun