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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Functionally distinct polymorphic sequences in the human genome that are targets for p53 transactivation
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Functionally distinct polymorphic sequences in the human genome that are targets for p53 transactivation

机译：人类基因组中功能独特的多态性序列，是p53反式激活的靶标

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摘要

The p53 tumor suppressor protein is a master regulatory transcription factor that coordinates cellular responses to DNA damage and cellular stress. Besides mutations in p53, or in proteins involved in the p53 response pathway, genetic variation in promoter response elements (REs) of p53 target genes is expected to alter biological responses to stress. To identify SNPs in p53 REs that may modify p53-controlled gene expression, we developed an approach that combines a custom bioinformatics search to identify candidate SNPs with functional yeast and mammalian cell assays to assess their effect on p53 transactivation. Among ≈2 million human SNPs, we identified >200 that seem to disrupt functional p53 REs. Eight of these SNPs were evaluated in functional assays to determine both the activity of the putative RE and the impact of the candidate SNPs on transactivation. All eight candidate REs were functional, and in every case the SNP pair exhibited differential transactivation capacities. Additionally, six of the eight genes adjacent to these SNPs are induced by genotoxic stress or are activated directly by transfection with p53 cDNA. Thus, this strategy efficiently identifies SNPs that may differentially affect gene expression responses in the p53 regulatory pathway.
机译：p53肿瘤抑制蛋白是一个主要的调控转录因子，可协调细胞对DNA损伤和细胞应激的反应。除了p53或p53应答途径中涉及的蛋白质中的突变外，p53靶基因的启动子应答元件（RE）的遗传变异有望改变对应激的生物学应答。为了在可能修饰p53调控基因表达的p53 REs中鉴定SNP，我们开发了一种方法，该方法结合了常规的生物信息学搜索以通过功能性酵母和哺乳动物细胞测定法鉴定候选SNP，以评估其对p53反式激活的影响。在大约200万人类SNP中，我们发现了200多个似乎破坏功能性p53 RE的分子。在功能测定中评估了这些SNP中的八个，以确定既定RE的活性和候选SNP对反式激活的影响。所有八个候选RE均具有功能，并且在每种情况下SNP对均表现出不同的反式激活能力。此外，与这些SNP相邻的8个基因中有6个是由基因毒性胁迫诱导的，或者是通过p53 cDNA转染直接激活的。因此，该策略有效地鉴定了可能在p53调节途径中差异影响基因表达反应的SNP。

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