Differential modulation of BRCA1 and BARD1 nuclear localisation and foci assembly by DNA damage
Differential modulation of BRCA1 and BARD1 nuclear localisation and foci assembly by DNA damage
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DOI：
10.1016/j.cellsig.2009.09.034
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发表时间：
2010-02-01
影响因子：
4.8
通讯作者：
Henderson, Beric R.
中科院分区：
文献类型：
--
作者：
Brodie, Kirsty M.;Henderson, Beric R.
BRCA 1/BARD 1异源二聚体调节基因组维持并有助于DNA损伤检查点反应。我们以前报道过BRCA 1和BARD 1可以在细胞核和细胞质之间穿梭。在这项研究中，我们评估了BRCA 1和BARD 1在不同类型的DNA损伤剂和化疗药物中的定位模式。在MCF-7细胞中，内源性BRCA 1在电离辐射（IR）后2小时在细胞核中短暂增加，而BARD 1不受影响。IR治疗没有诱导核出口的蛋白质，在以前的报告相反。UV辐射、依托泊苷或喜树碱引起的DNA损伤在处理后6 h引起核BARD 1的优先下调。蛋白酶体抑制剂MG 132阻断了紫外线依赖的核BARD 1的丢失，但未被来普霉素B阻断，表明BARD 1核降解而非核输出发生了变化。MG 132还在UV后6 h阻断BARD 1/BRCA 1核灶的分散，暗示蛋白酶体参与修复灶的解体。在细胞质中，BRCA 1和BARD 1被检测到在中心体，但它们的分布并没有被DNA损伤改变。BARD 1显示出比BRCA 1更强的线粒体积累，并且响应于DNA损伤而在线粒体处磷酸化。有丝分裂纺锤体毒物长春新碱和紫杉醇对BRCA 1或BARD 1亚细胞分布没有影响。我们的结论是，BARD 1的磷酸化，表达和定位模式的调节在细胞核和线粒体在不同形式的DNA损伤的反应，有助于BRCA 1/BARD 1在DNA修复和凋亡反应的作用。(C)2009 Elsevier Inc. All rights reserved.
The BRCA1/BARD1 heterodimer regulates genomic maintenance and contributes to the DNA damage checkpoint response. We previously reported that BRCA1 and BARD1 can shuttle between nucleus and cytoplasm. In this study, we evaluated the localisation patterns of BRCA1 and BARD1 in response to different types of DNA damaging agents and chemotherapeutic drugs. In MCF-7 cells, endogenous BRCA1 increased transiently in the nucleus at 2 h after ionising radiation (IR), whereas BARD1 was unaffected. IR treatment did not induce nuclear export of either protein, in contrast to previous reports. DNA damage by UV radiation, etoposide or camptothecin caused a preferential down-regulation of nuclear BARD1 at 6 h post-treatment. The UV-dependent loss of nuclear BARD1 was blocked by the proteasome inhibitor MG132, but not by leptomycin B, indicating a change in BARD1 nuclear degradation rather than nuclear export. MG132 also blocked the dispersal of BARD1/BRCA1 nuclear foci at 6 h after UV, implicating the proteasome in repair foci disassembly. In the cytoplasm, BRCA1 and BARD1 were detected at centrosomes but their distribution was not altered by DNA damage. BARD1 displayed a stronger mitochondria accumulation than BRCA1, and became phosphorylated at mitochondria in response to DNA damage. The mitotic spindle poisons vincristine and paclitaxel had no effect on BRCA1 or BARD1 subcellular distribution. We conclude that BARD1 phosphorylation, expression and localisation patterns are regulated in the nucleus and at mitochondria in response to different forms of DNA damage, contributing to the role of BRCA1/BARD1 in DNA repair and apoptotic responses. (C) 2009 Elsevier Inc. All rights reserved.