Role of NAD-dependent deacetylases SIRT1 and SIRT2 in radiation and cisplatin-induced cell death in vertebrate cells
Role of NAD-dependent deacetylases SIRT1 and SIRT2 in radiation and cisplatin-induced cell death in vertebrate cells
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DOI：
10.1111/j.1365-2443.2005.00836.x
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发表时间：
2005-04-01
期刊：
影响因子：
2.1
通讯作者：
Takata, M
中科院分区：
文献类型：
--
作者：
Matsushita, N;Takami, Y;Takata, M
酵母Sir2是一种依赖烟酰胺腺嘌呤二核苷酸（NAD）的组蛋白去乙酰化酶，在转录沉默、染色体稳定性、DNA损伤反应和衰老中起核心作用。在哺乳动物中，sir2样基因组成了一个由七个成员组成的家族，其功能在很大程度上是未知的。为了研究Sir2家族在脊椎动物中的作用，我们在缺乏p53的鸡细胞系DT40中破坏了Sir2的同源物SIRT1和SIRT2。SIRT1（-/-）和SIRT2（-/-）细胞均有轻度生长缺陷。菌落生存试验显示SIRT1（-/-）和SIRT2（-/-）细胞对顺铂分别有中度和轻度敏感性，而SIRT1（-/-）细胞对电离辐射（IR）敏感，而SIRT2（-/-）细胞不敏感。SIRT1和SIRT2双重缺失的细胞表现出与SIRT1（-/-）细胞相同水平的IR和顺铂敏感性。SIRT1（-/-）细胞在DNA双链断裂修复和G2/M检查点中似乎都没有缺陷，但在IR后比野生型细胞更容易诱导细胞死亡。此外，SIRT1-和sirt2缺陷细胞对包括顺铂和staurosporine在内的促凋亡刺激更敏感。我们的研究结果表明SIRT1和SIRT2以不依赖p53的方式调节应激诱导的细胞死亡途径。
Yeast Sir2 is a nicotinamide adenine dinucleotide (NAD)-dependent histone deacetylase that plays a central role in transcriptional silencing, chromosomal stability, DNA damage response and aging. In mammals, Sir2-like genes constitute a seven-member family whose function is largely unknown. To investigate the role of the Sir2 family in vertebrates, we have disrupted Sir2 homologues SIRT1 and SIRT2 in the p53-deficient chicken cell line DT40. Both SIRT1(-/-) and SIRT2(-/-) cells had mild growth defects. Colony survival assays showed moderate and mild sensitivity to cisplatin in SIRT1(-/-) and SIRT2(-/-) cells, respectively, while SIRT1(-/-), but not SIRT2(-/-) cells, were sensitive to ionizing radiation (IR). Cells rendered doubly deficient in SIRT1 and SIRT2 exhibited the same levels of IR and cisplatin sensitivity as SIRT1(-/-) cells. SIRT1(-/-) cells appeared to be defective neither in DNA double strand break repair nor in G2/M checkpoints, but were more susceptible to cell death induction following IR than wild-type cells. Furthermore, both SIRT1- and SIRT2-deficient cells were more sensitive to pro-apoptotic stimuli including cisplatin and staurosporine. Our results indicate that SIRT1 and SIRT2 regulate stress-induced cell death pathways in a p53-independent manner.