2026-04-17T15:53:15Zhttps://recercat.cat/oai/request

oai:recercat.cat:10230/607582025-12-18T01:13:08Zcom_2072_6col_2072_452952

00925njm 22002777a 4500 dc Anderson, Craig J. author López Bigas, Núria author Taylor, Martin S. author 2024-07-16T06:38:13Z 2024-07-16T06:38:13Z 2024 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. This work was supported by the MRC Human Genetics Unit core funding programme grants (MC_UU_00007/11, MC_UU_00007/16 and MC_UU_00035/2), MRC Toxicology Unit core funding (RG94521), Cancer Research UK Cambridge Institute funding (20412 and 22398) and European Molecular Biology Laboratory core funding. Support was also provided from specific research grants: PID2021-126568OB-I00 (CHEMOHEALTH) project, funded by the Spanish Ministry of Science (MCIN, AEI/10.13039/501100011033/); the Wellcome Trust (WT202878/B/16/Z); the European Research Council (615584 and 788937); Helmholtz NCT (DKFZ abteiling B270); the US NIH (R01GM083337); and the MRC equipment award (MC_PC_MR/X013677/1). Edinburgh Genomics is partly supported through core grants from the NERC (R8/H10/56), the MRC (MR/K001744/1) and the BBSRC (BB/J004243/1). J.C. was supported by a Wellcome Trust PhD Training Fellowship for Clinicians (WT223088/Z/21/Z) as part of the Edinburgh Clinical Academic Track (ECAT) programme. M.D.N. is a cross-disciplinary post-doctoral fellow supported by funding from the CRUK Brain Tumour Centre of Excellence Award (C157/A27589). O.P. was funded by a BIST PhD fellowship supported by the Secretariat for Universities and Research of the Ministry of Business and Knowledge of the Government of Catalonia and the Barcelona Institute of Science and Technology. V.S. was supported by an EMBL Interdisciplinary Postdoc (EIPOD) fellowship under Marie Skłodowska Curie actions COFUND (664726). P.-C.W. is supported by the ERC Starting Grant (BrainBreaks 949990) and a Helmholtz Young Investigator grant. S.J.A. received a Wellcome Trust PhD Training Fellowship for Clinicians (WT106563/Z/14/Z), an National Institute for Health and Care Research (NIHR) Clinical Lectureship and a CRUK Clinician Scientist Fellowship (RCCCSF-May23/100001). Cancer genomics DNA adducts Genome informatics Nucleotide excision repair Translesion synthesis Strand-resolved mutagenicity of DNA damage and repair