PAR和BRCA1-BARD1复合体互作介导的DNA损伤修复及抗肿瘤研究

Cells encounter enormous internal and external hazards during cell cycle. Breast Cancer Susceptibility Gene 1 (BRCA1) , as a tumor suppressor , participates in DNA damage response and protect the genomic stability. It has been shown that BARD1 is a functional partner of BRCA1, and BRCA1 and BARD1 form a stable complex . During the preliminary study, we found that the BRCT domain of BARD1 recognize poly(ADP-ribose) (PAR). The interaction between the BARD1 BRCT and PAR is important for targeting BRCA1 to the sites of DNA damage. Thus, we hypothesize that the interaction between PAR and the BRCA1-BARD1 complex plays a critical role for breast and ovarian tumor suppression. Thus, we plan to examine the role of protein PARylation in the DNA damage response, the molecular mechanism by which PAR regulates the BRCA1-BARD1 complex, and the functional defects of these BARD1 variants in PAR-related DNA damage response. The results may distinguish the pathogenic mutations from the rare benign polymorphisms and clarify the mechanism of DNA damage and repair. It is important for us to better understand the mechanism by which PAR and the BRCA1-BARD1 complex mediate DNA damage repair and provide a strong theoretical foundation, which may generate huge impacts for future breast and ovarian tumor prevention and therapeutics.

在细胞周期循环过程中细胞会遇到大量的内部和外部损伤。乳腺癌易感基因1（BRCA1）作为肿瘤抑制基因参与DNA损伤应答，保护基因组稳定性。研究表明，BARD1为BRCA1的功能性结合分子，它们能形成稳定的复合体，在前期研究中我们发现BARD1的BRCT结构域能够识别PAR，其间的相互作用对于靶向BRCA1到DNA损伤位点非常重要。因此我们提出假设，PAR和BRCA1-BARD1复合体的相互作用在抑制乳腺和卵巢肿瘤中起着关键作用。为此，本课题拟研究在DNA损伤应答中蛋白PAR化的作用及PAR调控BRCA1-BARD1复合体的分子机制及PAR相关的DNA损伤应答中BARD1突变体的功能缺陷。我们的研究结果将辨别致病突变与罕见的良性多态性，为阐明DNA修复损伤机制，加深PAR及BRCA1-BARD1介导的DNA损伤修复机制提供坚实的理论基础，这可能对未来的乳腺癌和卵巢癌的预防和治疗产生巨大的影响。