DNA碱基损伤是致癌突变的主要来源1。这种损伤可以通过病变分离2的过程产生链相突变模式和多等位基因变异。在这里,我们利用这些特性来揭示链不对称过程,比如复制和转录,形状DNA损伤和修复。尽管前导和滞后链复制3,4的机制不同,但我们观察到两条链的保真度和损伤耐受性相同。对于DNA的小烷基化加合物,我们的结果支持了一个模型,在这个模型中,相同的跨损伤聚合酶被即时招募到两个复制链,与庞大的紫外线诱导的加合物5的链不对称耐受性形成鲜明对比。在持续性损伤位点的多个不同突变的积累提供了定量全基因组和单碱基分辨率的修复过程的相对效率的手段。在多个尺度上,我们显示DNA损伤诱导的突变很大程度上是由DNA可及性对修复效率的影响形成的,而不是DNA损伤的梯度。最后,我们揭示了特定的基因组条件,可以通过破坏核苷酸切除修复的保真度来主动驱动致癌诱变。这些结果提供了有关链不对称机制如何形成的见解,DNA损伤的耐受性和修复,从而塑造癌症基因组进化。
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.