The novel role of Sirtuin 2 in regulation of transcription-associated DNA damage repair

Sirtuin 2 在调控转录相关 DNA 损伤修复中的新作用

• 批准号: 10443539
• 负责人: Fen Xia
• 金额: $ 32.03万
• 依托单位: UNIV OF ARKANSAS FOR MED SCIS
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-01 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10443539
• 关键词: Attenuated; Behavioral; Binding; Biological; Cancer Patient; Cell Death; Cell Differentiation process; Cell Nucleus; Cell Survival; Cell physiology; Cells; Cisplatin; Clinic; Cockayne Syndrome; Coupled; Cyclin-Dependent Kinase 5; DNA Damage; DNA Repair; Data; Deacetylase; Deacetylation; Foundations; Genetic; Genetic Transcription; Goals; In Vitro; Interruption; Ionizing radiation; Lung Adenocarcinoma; Malignant Neoplasms; Maps; Mediating; Mediator of activation protein; Metabolism; Modeling; Molecular; Nervous System Physiology; Neurologic; Neurologic Deficit; Neurons; Nuclear; Nucleotide Excision Repair; Oxidative Stress; Pathway interactions; Patients; Peripheral; Peripheral Nervous System Diseases; Pharmacology; Phase; Phosphorylation; Phosphorylation Inhibition; Proliferating; Proteins; Quality of life; Resistance; Role; Series; Serine; Signal Transduction; Sirtuins; Site; Spinal Ganglia; Testing; Toxic effect; Transcription-Coupled Repair; Transcriptional Regulation; Treatment Efficacy; Treatment Protocols; Tumor Suppression; base; biological adaptation to stress; cancer cell; cancer therapy; cytotoxicity; experimental study; homologous recombination; improved; in vivo; inhibitor; insight; irradiation; mouse model; neoplastic cell; neuronal survival; neurotoxicity; nicotinamide-beta-riboside; novel; novel strategies; prevent; recombinational repair; recruit; repaired; response; roscovitine; transcription factor; tumor

Project Summary The consequences of irradiation- and/or Cisplatin (IR/CisP)-induced neuronal toxicity, i.e., neurological function deficits, often irreversible and permanent, represent a daunting challenge when treating patients with cancer. The underlying mechanisms of toxicity remain poorly understood and the ability to selectively protect neuronal survival while not compromising tumor control following IR/CisP is lacking. This proposal aims to determine the mechanisms protecting neurons from IR/CisP-induced cytotoxicity, with the overarching goal to provide evidence supporting novel strategies to decrease their neurotoxicity, while maintaining therapy efficacy and improving patient quality of life. NAD+-dependent deacetylase sirtuin 2 (SIRT2), which is highly expressed in differentiated neurons, is involved in diverse cellular processes including metabolism, response to oxidative stress, and tumor suppression. Our preliminary study has discovered a novel signaling network that connects SIRT2 to transcription coupled- homologous recombination repair (TC-HRR) and -nucleotide excision repair (TC-NER) of DNA damage and neuronal cell resistance to IR/CisP-induced cytotoxicity. Furthermore, our data revealed that CSB, the key mediator for TC-HR/TC-NER, is directly deacetylated by SIRT2. Moreover, the cyclin-dependent kinase 5 (CDK5), which is involved in DNA damage signaling in neuron cells, phosphorylates and inhibits SIRT2 function in DNA repair and neuronal survival following IR/CisP. We hypothesize that SIRT2 activity, which is suppressed by CDK5-mediated phosphorylation, protects neurons against IR/CisP-induced DNA damage by enhancing CSB- directed TC-NER and TC-HRR, thereby attenuating neuronal cytotoxicity and neurological deficits. A series of in vitro and in vivo experiments are proposed to test this hypothesis: Aim 1 will determine whether CSB mediates SIRT2 promotion of TC-NER/TC-HRR and neuron survival following IR/CisP. Aim 2 will determine how CDK5 negatively regulates SIRT2 function in TC- NER/TC-HRR and neuron survival following IR/CisP. Aim 3 will test if pharmacologically targeting SIRT2 specifically attenuates neuronal deficits following IR/CisP-based cancer therapy. Results from these studies will provide insights into the biological role of SIRT2 and the molecular mechanisms regulating the repair of IR/CisP-induced DNA damage. We expect this study to lay the foundation for future research investigating the targeting of the CDK5/SIRT2-CSB signaling axis as a novel strategy to alleviate and/or prevent neurotoxicity in cancer patients who need IR/CisP therapy.

项目摘要 辐射和/或顺铂（IR/CisP）诱导的神经元毒性的后果， 也就是说，神经功能缺陷，往往是不可逆的和永久的，代表了一个艰巨的任务， 治疗癌症患者时的挑战。潜在的毒性机制仍然存在 我们对它的了解很少，并且有能力选择性地保护神经元的存活， 缺乏IR/CisP后的肿瘤控制。该提案旨在确定机制 保护神经元免受IR/CisP诱导的细胞毒性，总体目标是提供 证据支持新的策略，以减少其神经毒性，同时维持治疗 提高患者的生活质量。NAD+依赖性脱乙酰酶sirtuin 2（SIRT 2）， 在分化的神经元中高度表达，参与多种细胞过程 包括代谢、对氧化应激的反应和肿瘤抑制。我们的初步研究 发现了一种新的信号网络，将SIRT 2与转录偶联- DNA同源重组修复（TC-HRR）和核苷酸切除修复（TC-NER 损伤和神经元细胞对IR/CisP诱导的细胞毒性的抗性。此外，我们的数据 研究表明，CSB，TC-HR/TC-NER的关键介质，直接被SIRT 2脱乙酰化。 此外，细胞周期蛋白依赖性激酶5（CDK 5），参与DNA损伤信号转导， 神经元细胞，磷酸化并抑制SIRT 2在DNA修复和神经元存活中的功能 IR/CISP。我们假设SIRT 2的活性，这是抑制CDK 5介导的， 磷酸化，保护神经元免受IR/CisP诱导的DNA损伤，通过增强CSB- 定向的TC-NER和TC-HRR，从而减弱神经元细胞毒性和神经毒性， 赤字本论文通过一系列的体内、体外实验来验证这一假设： 将确定CSB是否介导SIRT 2促进TC-NER/TC-HRR和神经元存活 IR/CISP。目的2将确定CDK 5如何在TC中负调节SIRT 2功能。 NER/TC-HRR和IR/CisP后的神经元存活。Aim 3将测试目标是否 SIRT 2特异性减弱基于IR/CisP的癌症治疗后的神经元缺陷。结果 这些研究将为SIRT 2的生物学作用和SIRT 2的分子生物学作用提供新的见解。 调节IR/CisP诱导的DNA损伤修复的机制。我们希望这项研究能够奠定 为未来研究CDK 5/SIRT 2-CSB信号转导的靶向奠定基础 轴作为一种新的战略，以减轻和/或预防神经毒性的癌症患者谁需要 IR/CisP疗法。