Strand-resolved mutagenicity of DNA damage and repair

Mostra el registre complet Registre parcial de l'ítem

• dc.contributor.author Anderson, Craig J.
• dc.contributor.author López Bigas, Núria
• dc.contributor.author Taylor, Martin S.
• dc.date.accessioned 2024-07-16T06:38:13Z
• dc.date.available 2024-07-16T06:38:13Z
• dc.date.issued 2024
• dc.description.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.
• dc.description.sponsorship 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).
• dc.format.mimetype application/pdf
• dc.identifier.citation Anderson CJ, Talmane L, Luft J, Connelly J, Nicholson MD, Verburg JC, et al. Strand-resolved mutagenicity of DNA damage and repair. Nature. 2024 Jun;630(8017):744-51. DOI: 10.1038/s41586-024-07490-1
• dc.identifier.doi http://dx.doi.org/10.1038/s41586-024-07490-1
• dc.identifier.issn 0028-0836
• dc.identifier.uri http://hdl.handle.net/10230/60758
• dc.language.iso eng
• dc.publisher Nature Research
• dc.relation.ispartof Nature. 2024 Jun;630(8017):744-51
• dc.relation.projectID info:eu-repo/grantAgreement/EC/FP7/615584
• dc.relation.projectID info:eu-repo/grantAgreement/ES/3PE/PID2021-126568OB-I00
• dc.relation.projectID info:eu-repo/grantAgreement/EC/H2020/788937
• dc.rights © The Author(s) 2024. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
• dc.rights.accessRights info:eu-repo/semantics/openAccess
• dc.rights.uri http://creativecommons.org/licenses/by/4.0/
• dc.subject.keyword Cancer genomics
• dc.subject.keyword DNA adducts
• dc.subject.keyword Genome informatics
• dc.subject.keyword Nucleotide excision repair
• dc.subject.keyword Translesion synthesis
• dc.title Strand-resolved mutagenicity of DNA damage and repair
• dc.type info:eu-repo/semantics/article
• dc.type.version info:eu-repo/semantics/publishedVersion