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首页> 外文期刊>Oncogene >Transcriptional responses to ionizing radiation reveal that p53R2 protects against radiation-induced mutagenesis in human lymphoblastoid cells
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Transcriptional responses to ionizing radiation reveal that p53R2 protects against radiation-induced mutagenesis in human lymphoblastoid cells

机译：对电离辐射的转录反应表明，p53R2可以防止人类淋巴母细胞中辐射诱导的诱变

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The p53 protein has been implicated in multiple cellular responses related to DNA damage. Alterations in any of these cellular responses could be related to increased genomic instability. Our previous study has shown that mutations in p53 lead to hypermutability to ionizing radiation. To investigate further how p53 is involved in regulating mutational processes, we used 8K cDNA microarrays to compare the patterns of gene expression among three closely related human cell lines with different p53 status including TK6 (wild-type p53), NH32 (p53-null), and WTK1 (mutant p53). Total RNA samples were collected at 1, 3, 6, 9, and 24h after 10Gy -irradiation. Template-based clustering analysis of the gene expression over the time course showed that 464 genes are either up or downregulated by at least twofold following radiation treatment. In addition, cluster analyses of gene expression profiles among these three cell lines revealed distinct patterns. In TK6, 165 genes were upregulated, while 36 genes were downregulated. In contrast, in WTK1 75 genes were upregulated and 12 genes were downregulated. In NH32, only 54 genes were upregulated. Furthermore, we found several genes associated with DNA repair namely p53R2, DDB2, XPC, PCNA, BTG2, and MSH2 that were highly induced in TK6 compared to WTK1 and NH32. p53R2, which is regulated by the tumor suppressor p53, is a small subunit of ribonucleotide reductase. To determine whether it is involved in radiation-induced mutagenesis, p53R2 protein was inhibited by siRNA in TK6 cells and followed by 2Gy radiation. The background mutation frequencies at the TK locus of siRNA-transfected TK6 cells were about three times higher than those seen in TK6 cells. The mutation frequencies of siRNA-transfected TK6 cells after 2Gy radiation were significantly higher than the irradiated TK6 cells without p53R2 knock down. These results indicate that p53R2 was induced by p53 protein and is involved in protecting against radiation-induced mutagenesis.
机译：p53蛋白已经牵涉到与DNA损伤相关的多种细胞反应。这些细胞反应中的任何改变都可能与基因组不稳定性增加有关。我们以前的研究表明，p53突变导致电离辐射的超突变性。为了进一步研究p53如何参与调控突变过程，我们使用8K cDNA微阵列比较了三种不同p53状态密切相关的人类细胞系（包括TK6（野生型p53），NH32（p53-无效））中的基因表达模式。和WTK1（突变p53）。在10Gy辐照后的1、3、6、9和24小时收集总RNA样品。在整个时间过程中，基于模板的基因表达聚类分析表明，放疗后至少有两倍的基因上调或下调了464个基因。此外，这三种细胞系之间的基因表达谱的聚类分析揭示了不同的模式。在TK6中，165个基因被上调，而36个基因被下调。相反，在WTK1中，75个基因被上调，而12个基因被下调。在NH32中，只有54个基因被上调。此外，我们发现了几种与DNA修复相关的基因，即p53R2，DDB2，XPC，PCNA，BTG2和MSH2，与WTK1和NH32相比，它们在TK6中被高度诱导。受肿瘤抑制因子p53调控的p53R2是核糖核苷酸还原酶的一个小亚基。为了确定它是否参与辐射诱导的诱变，p53R2蛋白被TK6细胞中的siRNA抑制，然后进行2Gy辐射。 siRNA转染的TK6细胞TK基因座处的背景突变频率比TK6细胞中的背景突变频率高大约三倍。 siRNA转染的TK6细胞在2Gy辐射后的突变频率显着高于未击倒p53R2的TK6细胞。这些结果表明p53R2是由p53蛋白诱导的，并参与防止辐射诱导的诱变。

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