Missense mutations in cancer suppressor gene TP53 are colocalized with exonic splicing enhancers (ESEs)
Missense mutations in cancer suppressor gene TP53 are colocalized with exonic splicing enhancers (ESEs)
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DOI：
10.1016/j.mrfmmm.2004.04.014
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发表时间：
2004-10-04
影响因子：
2.3
通讯作者：
Amos, CI
中科院分区：
文献类型：
--
作者：
Gorlov, IP;Gorlova, OY;Amos, CI
突变数据库可以被视为基因功能组织的足迹，因此可以用来推断其功能组织。我们利用国际癌症研究机构 (IARC) 突变数据库研究了外显子剪接增强子 (ESE) 与肿瘤抑制基因 TP53 错义突变的关联。该研究的目标是：（i）验证有害错义突变与 ESE 共存的假设； (ii) 识别 TP53 开放阅读框 (ORF) 中潜在的功能性 ESE 位点。如果某些序列充当剪接增强子，那么该位点的核苷酸取代将干扰剪接，废除 p53 功能，并导致癌症易感性增加。因此，在显示 p53 突变的癌症中，与非功能性 ESE 基序相比，功能性 ESE 位点内预计会出现更多错义突变。通过多项统计测试，我们发现 TP53 中的错义突变与 ESE 强烈共定位。并且只有一小部分 ESE 站点为该关联做出了贡献。每个外显子通常有一个或两个 ESE，显示出与错义突变具有统计显着性关联 - 所谓的显着 ESE 位点。在许多方面，重要的 ESE 位点与那些不与错义突变无关的位点不同。我们发现重要 ESE 位点的位置是密码子依赖性的 - 重要 ESE 优先从密码子的第一个位置开始，而不显着 ESE 则不显示位置依赖性。与不显着的 ESE 相比，显着的 ESE 显示出更有限的序列集。这些发现表明，影响 ESE 位点的错义突变数量有限，我们的分析提供了对含有外显子增强子元件的位点类型的进一步了解。 (C) 2004 Elsevier B.V. 保留所有权利。
Mutation databases can be viewed as footprints of functional organization of a gene and thus can be used to infer its functional organization. We studied the association of exonic splicing enhancers (ESEs) with missense mutations in the tumor suppressor gene TP53 using the International Agency for Research on Cancer (IARC) mutation database. The goals of the study were: (i) to verify the hypothesis that deleterious missense mutations are colocalized with ESEs; (ii) to identify potentially functional ESE sites in the open reading frame (ORF) of the TP53. If some sequence functions as a splicing enhancer, then nucleotide substitutions in the site will disturb splicing, abrogate p53 function, and cause an increased susceptibility to cancer. Therefore, among cancers showing p53 mutations, more missense mutations are expected within functional ESE sites as compared to non-functional ESE motifs. Using several statistical tests, we found that missense mutations in TP53 are strongly colocalized with ESEs. and that only a small fraction of ESE sites contributes to the association. There are usually one or two ESEs per exon showing a statistically significant association with missense mutations - so-called significant ESE sites. In many respects significant ESE sites are different from those that do not show association with missense mutations. We found that positions of significant ESE sites are codon-dependent - significant ESEs preferentially start from the first position of a codon, whereas non-significant ESEs show no position dependence. Significant ESEs showed a more limited set of sequences compared to non-significant ESEs. These findings suggest that there is a limited number of missense mutations that influence ESE sites and our analysis provides further insight into the types of sites that harbor exonic enhancer elements. (C) 2004 Elsevier B.V. All rights reserved.