Ionizing Radiation-Induced DNA damage repair

PARP抑制剂已被用于BRCA1或BRCA2突变肿瘤的临床治疗。这个 PARP抑制剂的主要功能是抑制PARP1和PARP2介导的多(ADP-核糖基)，a 独特的翻译后修饰，主要在DNA损伤中诱导。PARP对PARP的抑制作用 抑制剂取消了DNA损伤反应因子的早期招募，并损害了DNA损伤修复。 由于PAR化是非常短暂的翻译后修饰，正常细胞有其他修复 补偿依赖于PAR化的DNA损伤反应丢失的机制。然而，一组 肿瘤细胞含有基因突变，如BRCA1/2突变，这些突变已经导致DSB受损 修理。通过额外的PARP抑制剂治疗来取消依赖于PAR化的DNA损伤反应， 这些肿瘤细胞会发生凋亡。因此，PARP抑制剂治疗选择性地用DNA杀死肿瘤细胞 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 抑制剂治疗。此外，积累的证据表明，PARP抑制剂治疗能够 抑制除BRCA肿瘤外的其他类型肿瘤的生长。因此，为了扩大治疗潜力， PARP抑制剂在肿瘤治疗中的应用，我们探索了用于PARP抑制剂治疗的生物标志物。有趣的是， 我们发现NAD的衍生物NADP在体外和体内都能抑制PAPS的活性。因此， 我们假设NADP是一种内源性PARP抑制物，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，包括化疗和放射治疗 心理治疗。在这个应用中，我们计划研究1)NADP在聚(ADP-核糖)依赖的DNA中的作用 损伤修复；2)NADP调节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，这项拟议的研究不仅将揭示DNA损伤修复的新分子机制， 而且还为癌症治疗找到了新的治疗方法。

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.