Atipairin Apichart, Ratanaphan Adisorn
Laboratory of Pharmaceutical Biotechnology, Department of Pharmaceutical Chemistry, Faculty of Pharmaceutical Sciences, Prince of Songkla University, Hat-Yai, Songkhla 90112, Thailand.
Breast Cancer (Auckl). 2011;5:201-8. doi: 10.4137/BCBCR.S8184. Epub 2011 Sep 25.
BRCA1 is a tumor suppressor protein involved in maintaining genomic integrity through multiple functions in DNA damage repair, transcriptional regulation, cell cycle checkpoint, and protein ubiquitination. The BRCA1-BARD1 RING complex has an E3 ubiquitin ligase function that plays essential roles in response to DNA damage repair. BRCA1-associated cancers have been shown to confer a hypersensitivity to chemotherapeutic agents. Here, we have studied the functional consequence of the in vitro E3 ubiquitin ligase activity and cisplatin sensitivity of the missense mutation D67Y BRCA1 RING domain. The D67Y BRCA1 RING domain protein exhibited the reduced ubiquitination function, and was more susceptible to the drug than the D67E or wild-type BRCA1 RING domain protein. This evidence emphasized the potential of using the BRCA1 dysfunction as an important determinant of chemotherapy responses in breast cancer.
BRCA1是一种肿瘤抑制蛋白，通过在DNA损伤修复、转录调控、细胞周期检查点和蛋白质泛素化等多种功能中发挥作用来维持基因组完整性。BRCA1 - BARD1环复合物具有E3泛素连接酶功能，在DNA损伤修复反应中起重要作用。已证明与BRCA1相关的癌症对化疗药物具有超敏性。在此，我们研究了错义突变D67Y BRCA1环结构域的体外E3泛素连接酶活性和顺铂敏感性的功能后果。D67Y BRCA1环结构域蛋白表现出泛素化功能降低，并且比D67E或野生型BRCA1环结构域蛋白对药物更敏感。这一证据强调了将BRCA1功能障碍作为乳腺癌化疗反应重要决定因素的潜力。
