英国爱丁堡大学Martin S. Taylor等研究人员合作揭示DNA损伤和修复的链分辨率的诱变性。2024年6月12日，《自然》杂志在线发表了这项成果。

研究人员表示，DNA碱基损伤是致癌突变的主要来源。这种损伤可通过病变分离过程产生链相突变模式和多拷贝变异。

研究人员利用这些特性来揭示链不对称过程（如复制和转录）是如何形成DNA损伤和修复的。尽管前导链和滞后链的复制机制各不相同，但研究人员观察到两条链的保真度和损伤耐受性完全相同。对于DNA的小型烷基化加合物，研究结果支持这样一种模式，即相同的转座聚合酶被即时招募到两条复制链上，这与大体积紫外线诱导加合物的链非对称耐受性形成了鲜明对比。在持续性病变部位积累多种不同的突变，为量化全基因组和单碱基分辨率修复过程的相对效率提供了手段。

在多个尺度上，研究人员发现DNA损伤诱导的突变主要受DNA可及性对修复效率的影响，而不是DNA损伤梯度的影响。最后，研究人员揭示了通过破坏核苷酸切除修复的保真度，而积极驱动致癌突变的特定基因组条件。这些结果让研究人员深入了解了链不对称机制，是如何支撑DNA损伤的形成、耐受和修复，从而影响癌症基因组演化的。

附：英文原文

Title: Strand-resolved mutagenicity of DNA damage and repair

Author: Anderson, Craig J., Talmane, Lana, Luft, Juliet, Connelly, John, Nicholson, Michael D., Verburg, Jan C., Pich, Oriol, Campbell, Susan, Giaisi, Marco, Wei, Pei-Chi, Sundaram, Vasavi, Connor, Frances, Ginno, Paul A., Sasaki, Takayo, Gilbert, David M., Lpez-Bigas, Nria, Semple, Colin A., Odom, Duncan T., Aitken, Sarah J., Taylor, Martin S.

Issue&Volume: 2024-06-12

Abstract: DNA base damage is a major source of oncogenic mutations1. Such damage can produce strand-phased mutation patterns and multiallelic variation through the process of lesion segregation2. Here we exploited these properties to reveal how strand-asymmetric processes, such as replication and transcription, shape DNA damage and repair. Despite distinct mechanisms of leading and lagging strand replication3,4, we observe identical fidelity and damage tolerance for both strands. For small alkylation adducts of DNA, our results support a model in which the same translesion polymerase is recruited on-the-fly to both replication strands, starkly contrasting the strand asymmetric tolerance of bulky UV-induced adducts5. The accumulation of multiple distinct mutations at the site of persistent lesions provides the means to quantify the relative efficiency of repair processes genome wide and at single-base resolution. At multiple scales, we show DNA damage-induced mutations are largely shaped by the influence of DNA accessibility on repair efficiency, rather than gradients of DNA damage. Finally, we reveal specific genomic conditions that can actively drive oncogenic mutagenesis by corrupting the fidelity of nucleotide excision repair. These results provide insight into how strand-asymmetric mechanisms underlie the formation, tolerance and repair of DNA damage, thereby shaping cancer genome evolution. How strand-asymmetric processes such as replication and transcription interact with DNA damage to drive mechanisms of repair and mutagenesis is explored.

DOI: 10.1038/s41586-024-07490-1

Source: https://www.nature.com/articles/s41586-024-07490-1