Strand-resolved mutagenicity of DNA damage and repair

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 transcriptio...

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Autores: Anderson, Craig J., López Bigas, Núria, Taylor, Martin S.
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2024
País:España
Institución:Universitat Pompeu Fabra
Repositorio:Repositorio Digital de la UPF
OAI Identifier:oai:repositori.upf.edu:10230/60758
Acceso en línea:http://hdl.handle.net/10230/60758
http://dx.doi.org/10.1038/s41586-024-07490-1
Access Level:acceso abierto
Palabra clave:Cancer genomics
DNA adducts
Genome informatics
Nucleotide excision repair
Translesion synthesis
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dc.title.none.fl_str_mv Strand-resolved mutagenicity of DNA damage and repair
title Strand-resolved mutagenicity of DNA damage and repair
spellingShingle Strand-resolved mutagenicity of DNA damage and repair
Anderson, Craig J.
Cancer genomics
DNA adducts
Genome informatics
Nucleotide excision repair
Translesion synthesis
title_short Strand-resolved mutagenicity of DNA damage and repair
title_full Strand-resolved mutagenicity of DNA damage and repair
title_fullStr Strand-resolved mutagenicity of DNA damage and repair
title_full_unstemmed Strand-resolved mutagenicity of DNA damage and repair
title_sort Strand-resolved mutagenicity of DNA damage and repair
dc.creator.none.fl_str_mv Anderson, Craig J.
López Bigas, Núria
Taylor, Martin S.
author Anderson, Craig J.
author_facet Anderson, Craig J.
López Bigas, Núria
Taylor, Martin S.
author_role author
author2 López Bigas, Núria
Taylor, Martin S.
author2_role author
author
dc.subject.none.fl_str_mv Cancer genomics
DNA adducts
Genome informatics
Nucleotide excision repair
Translesion synthesis
topic Cancer genomics
DNA adducts
Genome informatics
Nucleotide excision repair
Translesion synthesis
description 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.
publishDate 2024
dc.date.none.fl_str_mv 2024
2024
2024
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info:eu-repo/semantics/publishedVersion
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dc.identifier.none.fl_str_mv http://hdl.handle.net/10230/60758
http://dx.doi.org/10.1038/s41586-024-07490-1
url http://hdl.handle.net/10230/60758
http://dx.doi.org/10.1038/s41586-024-07490-1
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv Nature. 2024 Jun;630(8017):744-51
info:eu-repo/grantAgreement/EC/FP7/615584
info:eu-repo/grantAgreement/ES/3PE/PID2021-126568OB-I00
info:eu-repo/grantAgreement/EC/H2020/788937
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dc.publisher.none.fl_str_mv Nature Research
publisher.none.fl_str_mv Nature Research
dc.source.none.fl_str_mv reponame:Repositorio Digital de la UPF
instname:Universitat Pompeu Fabra
instname_str Universitat Pompeu Fabra
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spelling Strand-resolved mutagenicity of DNA damage and repairAnderson, Craig J.López Bigas, NúriaTaylor, Martin S.Cancer genomicsDNA adductsGenome informaticsNucleotide excision repairTranslesion synthesisDNA 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).Nature Research202420242024info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionapplication/pdfapplication/pdfhttp://hdl.handle.net/10230/60758http://dx.doi.org/10.1038/s41586-024-07490-1reponame:Repositorio Digital de la UPFinstname:Universitat Pompeu FabraInglésNature. 2024 Jun;630(8017):744-51info:eu-repo/grantAgreement/EC/FP7/615584info:eu-repo/grantAgreement/ES/3PE/PID2021-126568OB-I00info:eu-repo/grantAgreement/EC/H2020/788937© 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/.http://creativecommons.org/licenses/by/4.0/info:eu-repo/semantics/openAccessoai:repositori.upf.edu:10230/607582026-06-12T07:21:37Z
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