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Proteolytic control of DNA interstrand cross-link repair and genome integrity

DNA 链间交联修复和基因组完整性的蛋白水解控制

基本信息

批准号：
10358489
负责人：
Hyungjin Kim
金额：
$ 36.19万
依托单位：
STATE UNIVERSITY NEW YORK STONY BROOK
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-03-01 至 2024-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10358489
关键词：
Affect Animal Model Cancer Etiology Cancer cell line Cells Chemosensitization Complex Cytotoxic Chemotherapy DNA DNA Damage DNA Interstrand Cross-Link Repair DNA Repair DNA Repair Pathway DNA biosynthesis Data Defect Degradation Pathway Development FANCD2 protein FBXW7 gene Fanconi Anemia pathway Fanconi&apos s Anemia Genomic Instability Goals Health Homeostasis Human Impairment Intervention Investigation Isomerase Kinetics Knowledge Laboratories Lead Lesion Link Maintenance Malignant Neoplasms Mediating Molecular Molecular Conformation Molecular Genetics Monoubiquitination Pathogenesis Pathway interactions Peptidylprolyl Isomerase Phosphorylation Platinum Process Protein Dephosphorylation Protein Phosphatase 2A Regulatory Subunit PR53 Protein Subunits Proteins Proteolysis Public Health Regulation Research Role Signal Pathway Signal Transduction System Therapeutic Therapeutic Intervention Ubiquitin Work cancer predisposition cancer therapy cis trans isomerization cis-trans-Isomerases crosslink design genome integrity high risk improved interest malignant breast neoplasm mouse model multicatalytic endopeptidase complex neoplastic cell preservation protein degradation repaired response targeted treatment therapy outcome translational impact treatment response tumorigenesis ubiquitin-protein ligase

项目摘要

PROJECT SUMMARY Genome instability caused by incorrect DNA repair system is a major driver for tumorigenesis. Our long- term goal is to understand how cellular proteolysis controls the pathway responsible for repairing DNA damage, thereby preserving the integrity of the genome. Since homeostasis of DNA repair factors is critical for the activity of DNA repair, elucidating underlying mechanisms for the ubiquitin-proteolytic pathway in DNA repair is essential for understanding the etiology of cancer when it is derailed. We are interested in the mechanisms that link proteolysis to signaling of the Fanconi anemia (FA) DNA repair pathway, which deals with DNA interstrand cross-links (ICL) encountered during DNA replication. Its defects lead to a high risk of multiple cancers due to elevated genome instability, and its aberrant activity is known to influence therapeutic response to cytotoxic chemotherapy that utilizes DNA cross-linking agents including platinum. Thus, knowledge on molecular and genetic factors that control the FA pathway is expected to help us exploit their deregulation for the development of improved cancer therapeutics. One of the fundamental regulatory mechanisms for protein degradation is reversible phosphorylation of protein targets, which marks a protein to be destroyed by ubiquitin-proteasome system. We recently discovered the proteolytic signaling pathway of FAAP20, a key component of the FA core ubiquitin E3 ligase complex necessary for the FA pathway activation, and showed that deregulation of FAAP20 leads to a functional disruption of the FA core complex, impairing the ability of cells to repair DNA ICL lesions. Specifically, we defined SCFFBW7 as an ubiquitin E3 ligase complex responsible for phosphorylation-dependent FAAP20 degradation and demonstrated how its deregulation affects the FA pathway. Our preliminary studies also indicate that phosphorylation-dependent conformational change of FAAP20 regulated by cis-trans isomerase PIN1 modulates ubiquitin signaling of FAAP20 degradation, thereby determining the fate of the FA core complex and influencing the efficiency of DNA ICL repair. Herein, we propose to explicate PIN1-SCFFBW7 proteolytic signaling in controlling the FA pathway and its impact to genome instability. Specifically, we will (1) dissect the signaling pathway of FAAP20 degradation regulated by SCFFBW7, (2) elucidate the mechanisms by which PIN1-driven structural change of FAAP20 functions as a regulatory switch to control FAAP20 stability, and (3) determine the role of PIN1 in regulating DNA ICL repair and the therapeutic response of breast cancer to platinum via FA pathway signaling using cancer cell lines and a mouse model. Together, our studies are expected to reveal the first direct link between a highly deregulated PIN1-SCFFBW7 axis in human cancer and DNA ICL repair. This work will ultimately benefit human health by offering a unique opportunity to design therapeutic interventions that exploit aberrant DNA repair-associated proteolytic signaling in FA-related malignancy and cancer in general.

项目总结不正确的DNA修复系统引起的基因组不稳定是肿瘤发生的主要驱动因素。我们的长- 学期目标是了解细胞蛋白分解如何控制负责修复dna的途径。破坏，从而保持基因组的完整性。因为DNA修复因子的动态平衡对 DNA修复的活性，阐明DNA中泛素-蛋白分解途径的潜在机制当癌症脱轨时，修复对于理解癌症的病因是必不可少的。我们感兴趣的是将蛋白降解与Fanconi贫血(FA)DNA修复途径的信号联系起来的机制，该途径处理在DNA复制过程中遇到DNA链间交联链(ICL)。它的缺陷导致了高风险的由于基因组不稳定性升高而导致的多发性癌症，其异常活性已知会影响治疗对使用包括铂在内的DNA交联剂的细胞毒性化疗的反应。因此，控制FA途径的分子和遗传因素的知识有望帮助我们开发它们的放松管制，以发展改进的癌症疗法。其中一个基本的监管蛋白质降解的机制是蛋白质靶标的可逆磷酸化，这标志着蛋白质到被泛素-蛋白酶体系统破坏。我们最近发现了蛋白水解性信号通路 FAAP20，FA途径所必需的FA核心泛素E3连接酶复合体的关键成分激活，并表明FAAP20的解除调控导致FA核心复合体的功能中断，损害细胞修复DNA ICL损伤的能力。具体地说，我们将SCFFBW7定义为泛素E3 连接酶复合体负责依赖于磷酸化的FAAP20的降解，并展示了其放松调控会影响FA途径。我们的初步研究还表明，依赖于磷酸化的顺反异构酶Pin1调控FAAP20的构象变化调节泛素信号转导 FAAP20降解，从而决定FA核心复合体的命运并影响 DNA ICL修复。在此，我们建议阐明Pin1-SCFFBW7蛋白分解信号在控制FA中的作用途径及其对基因组不稳定性的影响。具体地说，我们将(1)剖析FAAP20的信号通路 SCFFBW7调控的降解，(2)阐明Pin1驱动结构变化的机制 FAAP20作为控制FAAP20稳定性的调节开关发挥作用，以及(3)确定Pin1在通过FA通路信号调节DNA ICL修复和乳腺癌对铂的治疗反应使用癌细胞系和小鼠模型。总而言之，我们的研究有望揭示第一个直接联系人类癌症中高度失控的Pin1-SCFFBW7轴与DNA ICL修复之间的关系。这项工作将通过提供独特的机会来设计治疗干预措施，从而最终造福于人类健康 FA相关恶性肿瘤和癌症中异常的DNA修复相关蛋白分解信号。