DNA damage-induced cytotoxicity is dissociated from BRCA1's DNA repair function but is dependent on its cytosolic accumulation.
DNA damage-induced cytotoxicity is dissociated from BRCA1's DNA repair function but is dependent on its cytosolic accumulation.
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DNA 损伤诱导的细胞毒性与 BRCA1 的 DNA 修复功能无关，但依赖于其胞质积累。
DOI：
10.1158/0008-5472.can-09-4713
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发表时间：
2010
期刊：
影响因子：
11.2
通讯作者：
Xia,Fen
中科院分区：
文献类型：
--
作者：
Wang,Hong;Yang,EddyS;Jiang,Juhong;Nowsheen,Somaira;Xia,Fen
肿瘤抑制基因BRCA1是一种核穿梭蛋白。然而，BRCA1的本地化在其功能调控中的作用仍有待阐明。鉴于BRCA1在DNA损伤修复中的核心作用，我们假设核内BRCA1的缺失会损害其在DNA修复中的核功能，从而导致对DNA损伤的细胞毒反应增强。在这项研究中，我们证明了DNA双链断裂的修复需要细胞核中的BRCA1。此外，将BRCA1隔离在胞浆中增强了人乳腺和结肠癌细胞对电离辐射或顺铂的细胞毒性反应。然而，利用双链断裂修复缺陷的BRCA1突变体对这种增强的细胞毒性机制的进一步遗传剖析意外地揭示了BRCA1的S功能在DNA修复中的作用与其对细胞对DNA损伤的敏感性的影响相分离。有趣的是，我们观察到DNA损伤诱导的细胞杀伤依赖于BRCA1在胞浆中的移位和积累。综上所述，这些数据表明，BRCA1的细胞质易位不仅在控制其DNA修复功能方面发挥着新的作用，而且在DNA损伤后的细胞死亡过程中也发挥着调节作用。对BRCA1胞浆易位诱导的细胞毒作用机制的进一步剖析揭示了细胞凋亡途径的参与。我们认为BRCA1核/胞浆穿梭的状态可能为预测肿瘤反应提供一个分子标志物，并可能成为一个潜在的新靶点，使癌细胞对基于DNA损伤的治疗敏感。癌症资源；70(15)；6258-67。©2010 AACR。
The tumor suppressor BRCA1 is a nuclear shuttling protein. However, the role of BRCA1 localization in the control of its functions remains to be elucidated. Given the central role of BRCA1 in DNA damage repair, we hypothesized that depletion of nuclear BRCA1 would compromise its nuclear function in DNA repair and thereby result in enhanced cytotoxic response to DNA damage. In this study, we showed that repair of DNA double-strand breaks required BRCA1 in the nucleus. In addition, sequestering BRCA1 in the cytosol enhanced the cytotoxic response to ionizing radiation or cisplatin in human breast and colon cancer cells. However, further genetic dissection of the mechanism of this enhanced cytotoxicity using BRCA1 mutants deficient in double-strand break repair unexpectedly revealed a dissociation of BRCA1's function in DNA repair from its effects on cellular sensitivity to DNA damage. Interestingly, we observed a dependence of the DNA damage–induced cell killing on the translocation and accumulation of BRCA1 in the cytosol. Together, these data suggest a novel role of cytoplasmic translocation of BRCA1, not only in controlling its DNA repair functions, but also in the regulation of cell death processes following DNA damage. Further dissection of the mechanism of cytotoxicity induced by BRCA1 cytoplasmic translocation revealed the involvement of the apoptotic pathway. We propose that the status of BRCA1 nuclear/cytoplasmic shuttling might provide a molecular marker to predict tumor response and a potential novel target to sensitize cancer cells to DNA damage–based therapy. Cancer Res; 70(15); 6258–67. ©2010 AACR.