Anticancer DNA intercalators cause p53-dependent mitochondrial DNA nucleoid re-modelling.
Anticancer DNA intercalators cause p53-dependent mitochondrial DNA nucleoid re-modelling.
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DOI：
10.1038/onc.2009.242
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发表时间：
2009-11-05
期刊：
影响因子：
8
通讯作者：
Poulton J
中科院分区：
文献类型：
--
作者：
Ashley N;Poulton J
许多抗癌药物，如阿霉素（DXR），嵌入癌细胞的核DNA，从而抑制其生长。然而，目前还不清楚这些药物如何与线粒体DNA（mtDNA）相互作用。利用培养细胞的细胞和分子研究，我们表明，DXR和其他DNA嵌入剂，如溴化乙锭，可以迅速嵌入到活细胞内的mtDNA，引起mtDNA类核蛋白的聚集和改变类核蛋白的分布。重塑的类核排除DXR并维持mtDNA合成，而非重塑的类核被DXR大量插入，这抑制了它们的复制，导致mtDNA耗尽。重塑伴随着广泛的线粒体延长或互连，并且在缺乏线粒体动力学的关键蛋白MFN 1和OPA 1的细胞中受到抑制。相反，重塑显着增加p53或ATM抑制，表明类核动力学和基因组DNA损伤反应之间的联系。总的来说，我们的研究结果表明，DNA嵌入剂可以触发常见的线粒体反应，这可能有助于与这些药物相关的显著临床毒性。
Many anti-cancer drugs, such doxorubicin (DXR), intercalate into nuclear DNA of cancer cells thereby inhibiting their growth. However, it is not well understood how such drugs interact with mitochondrial DNA (mtDNA). Using cell and molecular studies of cultured cells we show that DXR and other DNA intercalators such as ethidium bromide, can rapidly intercalate into mtDNA within living cells, causing aggregation of mtDNA nucleoids and altering the distribution of nucleoid proteins. Remodelled nucleoids excluded DXR and maintained mtDNA synthesis, whereas non-remodelled nucleoids became heavily intercalated with DXR, which inhibited their replication leading to mtDNA depletion. Remodelling was accompanied by extensive mitochondrial elongation or interconnection, and was suppressed in cells lacking MFN 1 and OPA1, key proteins for mitochondrial dynamics. In contrast, remodelling was significantly increased by p53 or ATM inhibition, indicating a link between nucleoid dynamics and the genomic DNA damage response. Collectively, our results show that DNA intercalators can trigger a common mitochondrial response, which likely contributes to the marked clinical toxicity associated with these drugs.