Departments of Radiation Oncology and Cancer Biology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-5671, USA.
Cancer Res. 2011 Aug 15;71(16):5546-57. doi: 10.1158/0008-5472.CAN-10-3423. Epub 2011 Jul 8.
Subcellular localization regulates BRCA1 function, and BRCA1 is exported to the cytoplasm following DNA damage in a p53-dependent manner. Because more than 50% of solid tumors harbor p53 mutations, it is possible that genetically wild-type (wt) BRCA1 is functionally abnormal through compromised nuclear-cytoplasmic shuttling in sporadic breast cancer patients with dysfunctional p53. In this study, we have investigated the mechanisms of p53-dependent BRCA1 subcellular distribution and DNA damage-induced nuclear export, as well as the impact on the resulting cytotoxic response to therapy in human breast cancer. We first show that p53 mediates BRCA1 nuclear export via protein-protein binding, rather than by modulation of its transcription. Furthermore, it is the C-terminal (BRCT) region of BRCA1 that is critical for its interaction with p53, and p53 may promote BRCA1 nuclear export by interrupting the association of BRCA1 with BARD1. In sporadic breast cancer specimens, dysfunctional p53 strongly correlates with nuclear retention of sequence-verified wt BRCA1. This p53-dependent BRCA1 shuttling determines cellular susceptibility to DNA damage as augmentation of cytosolic BRCA1 significantly enhances cancer cell susceptibility to ionizing radiation. Taken together, our data suggest that p53 dysfunction compromises nuclear export of wt BRCA1 as a mechanism to increase cellular resistance to DNA damage in sporadic breast cancer. We propose that targeting nuclear BRCA1 to the cytoplasm may offer a unique strategy to sensitize p53-deficient sporadic breast cancers to DNA damage-based therapy.
亚细胞定位调节 BRCA1 功能，并且 BRCA1 在 DNA 损伤后通过 p53 依赖性方式被输出到细胞质中。由于超过 50%的实体瘤携带有 p53 突变，因此在 p53 功能失调的散发性乳腺癌患者中，具有野生型（wt）BRCA1 的基因可能由于核质穿梭功能异常而导致功能异常。在这项研究中，我们研究了 p53 依赖性 BRCA1 亚细胞分布和 DNA 损伤诱导的核输出的机制，以及对人乳腺癌中治疗引起的细胞毒性反应的影响。我们首先表明 p53 通过蛋白-蛋白结合介导 BRCA1 核输出，而不是通过调节其转录。此外，BRCA1 的 C 端（BRCT）区域对于其与 p53 的相互作用至关重要，并且 p53 可能通过中断 BRCA1 与 BARD1 的结合来促进 BRCA1 的核输出。在散发性乳腺癌标本中，功能失调的 p53 与经序列验证的 wt BRCA1 的核内保留强烈相关。这种 p53 依赖性 BRCA1 穿梭决定了细胞对 DNA 损伤的敏感性，因为细胞溶质 BRCA1 的增加显著增强了癌细胞对电离辐射的敏感性。总之，我们的数据表明，p53 功能失调会损害 wt BRCA1 的核输出，作为增加散发性乳腺癌细胞对 DNA 损伤的抵抗力的机制。我们提出将核 BRCA1 靶向细胞质可能为基于 DNA 损伤的治疗使 p53 缺陷型散发性乳腺癌敏感提供一种独特的策略。
