PDF(Pubmed)
Abstract：
Recent studies have revealed that arginine is the most favorable target of amino acid alteration in most cancer types and it has been suggested that the high preference for arginine mutations reflects the critical roles of this amino acid in the function of proteins. High rates of mutations of arginine residues in cancer, however, might also be due to increased mutability of arginine codons of the CGN family as the CpG dinucleotides of these codons may be methylated. In the present work we have analyzed spectra of single base substitutions of cancer genes (oncogenes, tumor suppressor genes) and passenger genes in cancer tissues to assess the contributions of CpG hypermutability and selection to arginine mutations. Our studies have shown that arginines encoded by the CGN codon family display higher rates of mutation in both cancer genes and passenger genes than arginine codons AGA and AGG that are devoid of CpG dinucleotide, suggesting that the predominance of arginine mutations in cancer is primarily due to CpG hypermutability, rather than selection for arginine replacement. Nevertheless, our results also suggest that CGN codons for arginines may serve as Achilles\' heels of cancer genes. CpG hypermutability of key arginines of proto-oncogenes, leading to high rates of recurrence of driver mutations, contributes significantly to carcinogenesis. Similarly, our results indicate that hypermutability of the CpG dinucleotide of CGA codons (converting them to TGA stop codons) contributes significantly to recurrent truncation and inactivation of tumor suppressor genes.
摘要：
最近的研究表明，精氨酸是大多数癌症类型中氨基酸改变的最有利靶标，并且已经表明，对精氨酸突变的高度偏好反映了该氨基酸在蛋白质功能中的关键作用。癌症中精氨酸残基的高突变率，然而,也可能是由于CGN家族的精氨酸密码子的突变性增加，因为这些密码子的CpG二核苷酸可能被甲基化。在目前的工作中，我们分析了癌症基因的单碱基替换的光谱（癌基因，肿瘤抑制基因）和癌组织中的过客基因，以评估CpG高突变性和选择对精氨酸突变的贡献。我们的研究表明，与缺乏CpG二核苷酸的精氨酸密码子AGA和AGG相比，CGN密码子家族编码的精氨酸在癌症基因和过客基因中显示出更高的突变率。表明精氨酸突变在癌症中占主导地位主要是由于CpG的高突变性，而不是选择精氨酸替代。然而，我们的结果还表明，精氨酸的CGN密码子可能是癌症基因的致命弱点。原癌基因关键精氨酸的CpG超突变性，导致驱动突变的高复发率，对致癌作用有重要贡献。同样，我们的结果表明，CGA密码子的CpG二核苷酸的超突变性（将其转换为TGA终止密码子）显着导致肿瘤抑制基因的反复截短和失活。
