Mutational signatures of redox stress in yeast single-strand DNA and of aging in human mitochondrial DNA share a common feature

Redox stress is a major hallmark of cancer. Analysis of thousands of sequenced cancer exomes and whole genomes revealed distinct mutational signatures that can be attributed to specific sources of DNA lesions. Clustered mutations discovered in several cancer genomes were linked to single-strand DNA (ssDNA) intermediates in various processes of DNA metabolism. Previously, only one clustered mutational signature had been clearly associated with a subclass of ssDNA-specific apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like (APOBEC) cytidine deaminases. Others remain to be elucidated. We report here deciphering of the mutational spectra and mutational signature of redox stress in ssDNA of budding yeast and the signature of aging in human mitochondrial DNA. We found that the predominance of C to T substitutions is a common feature of both signatures. Measurements of the frequencies of hydrogen peroxide–induced mutations in proofreading-defective yeast mutants supported the conclusion that hydrogen peroxide–induced mutagenesis is not the result of increased DNA polymerase misincorporation errors but rather is caused by direct damage to DNA. Proteins involved in modulation of chromatin status play a significant role in prevention of redox stress–induced mutagenesis, possibly by facilitating protection through modification of chromatin structure. These findings provide an opportunity for the search and identification of the mutational signature of redox stress in cancers and in other pathological conditions and could potentially be used for informing therapeutic decisions. In addition, the discovery of such signatures that may be present in related organisms should also advance our understanding of evolution.

氧化还原应激（Redox stress）是癌症的核心标志之一。对数千个已测序的癌症外显子组与全基因组开展分析，可揭示出可归因为特定DNA损伤来源的独特突变特征。在多种癌症基因组中发现的成簇突变，与DNA代谢各进程中的单链DNA（single-strand DNA, ssDNA）中间体存在关联。此前，仅有一类成簇突变特征被明确关联至单链DNA特异性载脂蛋白B mRNA编辑酶催化多肽样（apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like, APOBEC）胞苷脱氨酶的亚类，其余此类突变特征仍有待阐明。本研究解析了出芽酵母（budding yeast）单链DNA中氧化还原应激的突变谱与突变特征，以及人类线粒体DNA（mitochondrial DNA）中的衰老相关突变特征。研究发现，C至T碱基替换的占比优势为这两类突变特征的共同特点。针对校对缺陷（proofreading-defective）的酵母突变体中过氧化氢诱导突变频率的检测结果，支持了如下结论：过氧化氢诱导的诱变效应并非源于DNA聚合酶错配掺入错误的增加，而是由DNA直接损伤所引发。参与染色质状态调控的蛋白质在预防氧化还原应激诱导的诱变过程中发挥关键作用，其可能通过修饰染色质结构来促进保护作用。上述发现为在癌症及其他病理状态中搜寻与鉴定氧化还原应激的突变特征提供了新的契机，并有潜力为临床治疗决策提供参考依据。此外，在相关生物中发现这类突变特征，也将进一步推动我们对进化过程的认知。