在多细胞生物中,体细胞突变代表了细胞在其局部微环境中经历的过去化学和生化扰动的永久记录。类似于永久记录装置,每次复制,基因组DNA积累的突变模式反映:i)DNA损伤的序列环境依赖性形成,由于环境或内源性反应性物种,包括自发过程;ii)DNA修复途径的活性,which,根据病变的类型,可以擦除,忽略或加剧该DNA损伤的诱变后果;和iii)合成新生基因组拷贝的复制机制的选择。这三个因素导致丰富的轮廓序列上下文相关的突变谱,从外表来看,对于大多数个体形式的DNA损伤是不同的。这样的诱变遗产,如果解码得当,可以揭示基因组改变事件的当地历史,如化学品或病原体暴露,代谢应激,和炎症,这反过来可以提供遗传疾病的根本原因和机制的指示。现代工具使我们能够对调节突变过程的细胞因子和途径进行深入的机械理解,反过来,提供更好的诊断和预后生物标志物的机会,更好的暴露风险评估,甚至可行的治疗目标。这个观点的目标是提出一个自下而上的,整合病变复制的贡献的以病变为中心的诱变框架,损伤修复和损伤形成,以解释暴露于诱变剂后基因组中出现的复杂突变谱。这里展示了经过充分研究的肝癌原黄曲霉毒素B1的突变光谱,作为具体例子,但其含义是可以概括的。
In a multicellular organism, somatic mutations represent a permanent record of the past chemical and biochemical perturbations experienced by a cell in its local microenvironment. Akin to a perpetual recording device, with every replication, genomic DNA accumulates mutations in patterns that reflect: i) the sequence context-dependent formation of DNA damage, due to environmental or endogenous reactive species, including spontaneous processes; ii) the activity of DNA repair pathways, which, depending on the type of lesion, can erase, ignore or exacerbate the mutagenic consequences of that DNA damage; and iii) the choice of replication machinery that synthesizes the nascent genomic copy. These three factors result in a richly contoured sequence context-dependent mutational spectrum that, from appearances, is distinct for most individual forms of DNA damage. Such a mutagenic legacy, if appropriately decoded, can reveal the local history of genome-altering events such as chemical or pathogen exposures, metabolic stress, and inflammation, which in turn can provide an indication of the underlying causes and mechanisms of genetic disease. Modern tools have positioned us to develop a deep mechanistic understanding of the cellular factors and pathways that modulate a mutational process and, in turn, provide opportunities for better diagnostic and prognostic biomarkers, better exposure risk assessment and even actionable therapeutic targets. The goal of this Perspective is to present a bottom-up, lesion-centric framework of mutagenesis that integrates the contributions of lesion replication, lesion repair and lesion formation to explain the complex mutational spectra that emerge in the genome following exposure to mutagens. The mutational spectra of the well-studied hepatocarcinogen aflatoxin B1 are showcased here as specific examples, but the implications are meant to be generalizable.