The roles of transcription and genotoxins underlying p53 mutagenesis in vivo.
The roles of transcription and genotoxins underlying p53 mutagenesis in vivo.
复制标题
转录和基因毒素在体内 p53 诱变中的作用。
DOI：
10.1093/carcin/bgr177
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发表时间：
2011
期刊：
影响因子：
4.7
通讯作者：
Reschke,DennisK
中科院分区：
文献类型：
--
作者：
Wright,BarbaraE;Schmidt,KarenH;Hunt,AaronT;Lodmell,JStephen;Minnick,MichaelF;Reschke,DennisK
Transcription drives supercoiling which forms and stabilizes single-stranded (ss) DNA secondary structures with loops exposing G and C bases that are intrinsically mutable and vulnerable to non-enzymatic hydrolytic reactions. Since many studies in prokaryotes have shown direct correlations between the frequencies of transcription and mutation, we conductedin silicoanalyses using the computer program,mfg, which simulates transcription and predicts the location of known mutable bases in loops of high-stability secondary structures.Mfganalyses of thep53tumor suppressor gene predicted the location of mutable bases and mutation frequencies correlated with the extent to which these mutable bases were exposed in secondary structures.In vitroanalyses have now confirmed that the 12 most mutable bases inp53are in fact located in predicted ssDNA loops of these structures. Data show that genotoxins have two independent effects on mutagenesis and the incidence of cancer: Firstly, they activatep53transcription, which increases the number of exposed mutable bases and also increases mutation frequency. Secondly, genotoxins increase the frequency of G-to-T transversions resulting in a decrease in G-to-A and C mutations. This precise compensatory shift in the ‘fate’ of G mutations has no impact on mutation frequency. Moreover, it is consistent with our proposed mechanism of mutagenesis in which the frequency of G exposure in ssDNA via transcription is rate limiting for mutation frequencyin vivo.
