Molecular Mechanisms of BRCA1-Dependent DNA Damage Response and Tumorogenesis

描述(申请人提供)：BRCA1和BRCA2是抑制家族性乳腺癌和卵巢癌的核多肽。越来越多的证据表明，BRCA1和BRCA2都参与了DNA损伤反应并维持了基因组的稳定性。BRCA1和BRCA2的突变破坏了DNA损伤修复，并在基因毒性应激下导致基因组不稳定，最终导致肿瘤的发生。然而，BRCA1和BRCA2参与DNA损伤反应的分子机制仍然不清楚，这损害了家族性乳腺癌和卵巢癌的放射治疗。最近，我们和其他人发现PALB2是一个重要的接头，在线性DNA损伤修复途径中连接BRCA1和BRCA2。此外，像BRCA1和BRCA2一样，PALB2的胚系突变与家族性乳腺癌和卵巢癌有关，这表明PALB2是一种真正的肿瘤抑制因子。为了阐明这个BRCA通路在DNA损伤反应和肿瘤抑制中的作用，我们的研究集中在PALB2的分子机制上。使用无偏蛋白亲和纯化方法，我们鉴定了几个PALB2合作伙伴。我们的初步研究表明，PALB2是一种双链DNA结合蛋白，在DNA损伤诱导的组蛋白乙酰化和染色质重塑中发挥重要作用。在本项目中，我们计划：1)剖析PALB2在DNA损伤诱导染色质重塑中的分子机制；2)检测与癌症相关的PALB2突变的功能缺陷；3)探索防止PALB2缺乏诱导肿瘤发生的新的治疗策略。这些研究不仅将揭示BRCA途径在DNA损伤反应中的分子机制，而且将把我们从基础科学研究中获得的知识转化为肿瘤预防。

DESCRIPTION (provided by applicant): BRCA1 and BRCA2 are nuclear polypeptides to suppress familial breast and ovarian cancers. Accumulated evidence suggests that both BRCA1 and BRCA2 participate in DNA damage response and maintain genomic stability. Mutations of BRCA1 and BRCA2 abrogate DNA damage repair and cause genomic instability under genotoxic stress, which eventually induces tumorigenesis. However, the molecular mechanism by which BRCA1 and BRCA2 participate in DNA damage response remain elusive, which impairs the irradiation of familial breast and ovarian cancers. Recently, we and others identified that PALB2 is an important adaptor that links BRCA1 and BRCA2 in a linear DNA damage repair pathway. Moreover, like BRCA1 and BRCA2, germline mutations of PALB2 are associated with familial breast and ovarian cancers, suggesting that PALB2 is a bona fide tumor suppressor. To elucidate the function of this BRCA pathway in DNA damage response and tumor suppression, our research focuses on the molecular mechanism of PALB2. Using unbiased protein affinity purification approach, we identified several PALB2 partners. Our preliminary study indicates that PALB2 is a double-strand DNA binding protein and plays an important role in DNA damage-induced histone acetylation and chromatin remodeling. In this project, we plan to: 1) dissect the molecular mechanism of PALB2 in DNA damage-induced chromatin remodeling; 2) examine the functional defects of cancer-associated PALB2 mutations; 3) explore novel therapeutic strategies to prevent PALB2 deficiency-induced tumorigenesis. These studies will not only reveal the molecular mechanism of BRCA pathway in DNA damage response, but also translate our knowledge from basic science research into tumor prevention.