Strand-resolved mutagenicity of DNA damage and repair

• 成果类型: Article
• 署名作者: 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.; Lopez-Bigas, Nuria; Semple, Colin A.; Odom, Duncan T.; Aitken, Sarah J.; Taylor, Martin S.
• 署名单位: UK Research & Innovation (UKRI); Medical Research Council UK (MRC); University of Edinburgh; University of Cambridge; UK Research & Innovation (UKRI); Medical Research Council UK (MRC); University of Edinburgh; University of Edinburgh; Barcelona Institute of Science & Technology; Institute for Research in Biomedicine - IRB Barcelona; Helmholtz Association; German Cancer Research Center (DKFZ); European Molecular Biology Laboratory (EMBL); European Bioinformatics Institute; Cancer Research UK; University of Cambridge; CRUK Cambridge Institute; Helmholtz Association; German Cancer Research Center (DKFZ); Pompeu Fabra University; ICREA; CIBER - Centro de Investigacion Biomedica en Red; CIBERONC; Instituto de Salud Carlos III; University of Cambridge; University of Cambridge
• 刊物名称: Nature
• ISSN/ISSBN: 0028-6272
• DOI: 10.1038/s41586-024-07490-1
• 发表日期: 2024-06-20
• 页码: 744-+
• 关键词: genome-wide analysis; mutational signatures; reveal mechanisms; excision-repair; read alignment; replication; binding; mutagenesis; chromatin; ctcf

摘要

DNA base damage is a major source of oncogenic mutations(1). Such damage can produce strand-phased mutation patterns and multiallelic variation through the process of lesion segregation(2). 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 replication(3,4), 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 adducts(5). 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.