Ionizing Radiation-Induced DNA damage repair

电离辐射诱导的 DNA 损伤修复

• 批准号: 10475652
• 负责人: Yilun Liu
• 金额: $ 40.96万
• 依托单位: BECKMAN RESEARCH INSTITUTE/CITY OF HOPE
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-05-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10475652
• 关键词: Apoptosis; BRCA mutations; BRCA1 Mutation; BRCA2 Mutation; Back; Biological Markers; Cell Cycle Arrest; Cell Cycle Progression; Cells; Chemical Structure; Chemotherapy and/or radiation; Clinical Research; Clinical Treatment; Clinical Trials; DNA; DNA Damage; DNA Double Strand Break; DNA Repair; DNA Sequence Alteration; Defect; Double Strand Break Repair; FDA approved; Growth; Impairment; In Vitro; Ionizing radiation; Lead; Lesion; Malignant Neoplasms; Malignant neoplasm of ovary; Mediating; Molecular; NAD+ kinase; NADP; Normal Cell; Phosphoric Monoester Hydrolases; Phosphorylation; Post-Translational Protein Processing; Radiation induced double strand break; Radiation therapy; Regulation; Research Project Grants; Role; Signal Transduction; Testing; Therapeutic; Treatment-Related Cancer; antagonist; cancer cell; cancer therapy; chemotherapy; design; experimental study; in vivo; inhibitor; neoplastic cell; novel; novel therapeutic intervention; ovarian neoplasm; potential biomarker; recruit; repaired; response; sensor; triple-negative invasive breast carcinoma; tumor; tumor DNA

PARP inhibitors have been used in the clinical treatment for tumors with BRCA1 or BRCA2 mutations. The major function of PARP inhibitors is to suppress PARP1 and PARP2 mediated poly(ADP-ribosyl)ation, a unique posttranslational modification, mainly induced in DNA damage. Suppression of PARylation by PARP inhibitors abolishes early recruitment of DNA damage response factors and impairs DNA damage repair. Because PARylation is a very transient posttranslational modification, normal cells have other repair mechanism to compensate for the loss of PARylation-dependent DNA damage response. However, a set of tumor cells harbor genetic mutations, such as BRCA1/2 mutations, which have already led to impaired DSB repair. With additional PARP inhibitor treatment to abolish PARylation-dependent DNA damage response, these tumor cells will undergo apoptosis. Thus, PARP inhibitor treatment selectively kills tumor cells with DNA damage repair defects, such as BRCA tumors. However, recent clinical trials suggest that only a set of BRCA tumors respond effectively to the PARP inhibitor treatment. Moreover, accumulated evidence indicates that PARP inhibitor treatment is able to suppress the growth of other types of tumor besides BRCA tumors. Thus, to extend the therapeutic potential of PARP inhibitors in cancer treatment, we explored biomarkers for the PARP inhibitor treatment. Interestingly, we found that NADP+, an NAD+ derivative, can suppress the activity of PARPs both in vitro and in vivo. Thus, we hypothesize that NADP+ is an endogenous PARP inhibitor, and the high level of NADP+ in tumor cells is able to sensitize tumor cells for DNA damaging related cancer therapy, including chemotherapy and radiation therapy. In this application, we plan to examine 1) the role of NADP+ in poly(ADP-ribosyl)ation-dependent DNA damage repair; 2) the molecular mechanism that regulates the cellular level of NADP+; 3) the role of NADP+ in sensitizing tumor cells to DNA damaging-associated cancer therapy. Taken together, the proposed study will not only reveal novel molecular mechanism in DNA damage repair, but also identify novel therapeutic approach for cancer treatment.

PARP抑制剂已用于BRCA 1或BRCA 2突变肿瘤的临床治疗。的 PARP抑制剂的主要功能是抑制PARP 1和PARP 2介导的聚（ADP-核糖基）化， 独特的翻译后修饰，主要在DNA损伤中诱导。PARP抑制PAR化 抑制剂消除了DNA损伤应答因子的早期募集并损害DNA损伤修复。 由于PAR化是一种非常短暂的翻译后修饰，正常细胞具有其他修复功能。 这是一种补偿PAR化依赖性DNA损伤反应损失的机制。然而，一套 肿瘤细胞携带基因突变，如BRCA 1/2突变，这已经导致DSB受损 修复.通过额外的PARP抑制剂治疗来消除PAR化依赖性DNA损伤反应， 这些肿瘤细胞将经历凋亡。因此，PARP抑制剂治疗选择性地杀死具有DNA的肿瘤细胞。 损伤修复缺陷，如BRCA肿瘤。 然而，最近的临床试验表明，只有一组BRCA肿瘤对PARP有效反应 抑制剂处理。此外，累积的证据表明，PARP抑制剂治疗能够 抑制BRCA肿瘤以外的其他类型肿瘤的生长。因此，为了扩展 为了研究PARP抑制剂在癌症治疗中的作用，我们探索了PARP抑制剂治疗的生物标志物。有趣的是， 我们发现NADP+，一种NAD+衍生物，在体外和体内都能抑制PARP的活性。因此，在本发明中， 我们假设NADP+是一种内源性PARP抑制剂，肿瘤细胞中高水平的NADP+是 能够使肿瘤细胞对DNA损伤相关的癌症治疗敏感，包括化疗和放疗 疗法在本申请中，我们计划研究1）NADP+在聚（ADP-核糖基）阳离子依赖性DNA中的作用 损伤修复; 2）调节NADP+细胞水平的分子机制; 3）NADP+在 使肿瘤细胞对DNA损伤相关的癌症治疗敏感。 综上所述，该研究不仅将揭示DNA损伤修复的新分子机制， 而且还为癌症治疗确定了新的治疗方法。