Strand-resolved mutagenicity of DNA damage and repair

Craig J. Anderson, Lana Talmane, Juliet Luft, John Connelly, Michael D. Nicholson, Jan C. Verburg, Oriol Pich, Susan Campbell, Marco Giaisi, Pei-Chi Wei, Vasavi Sundaram, Frances Connor, Paul A. Ginno, Takayo Sasaki, David M. Gilbert, Núria López-Bigas, Colin A. Semple, Duncan T. Odom (), Sarah J. Aitken () and Martin S. Taylor ()
Additional contact information
Craig J. Anderson: University of Edinburgh
Lana Talmane: University of Edinburgh
Juliet Luft: University of Edinburgh
John Connelly: University of Edinburgh
Michael D. Nicholson: University of Edinburgh
Jan C. Verburg: University of Edinburgh
Oriol Pich: The Barcelona Institute of Science and Technology
Susan Campbell: University of Edinburgh
Marco Giaisi: German Cancer Research Center (DKFZ)
Pei-Chi Wei: German Cancer Research Center (DKFZ)
Vasavi Sundaram: European Bioinformatics Institute
Frances Connor: University of Cambridge
Paul A. Ginno: German Cancer Research Center (DKFZ)
Takayo Sasaki: San Diego Biomedical Research Institute
David M. Gilbert: San Diego Biomedical Research Institute
Núria López-Bigas: The Barcelona Institute of Science and Technology
Colin A. Semple: University of Edinburgh
Duncan T. Odom: University of Cambridge
Sarah J. Aitken: University of Cambridge
Martin S. Taylor: University of Edinburgh

Nature, 2024, vol. 630, issue 8017, 744-751

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41586-024-07490-1

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