Mutational signatures are jointly shaped by DNA damage and repair
Mutational signatures are jointly shaped by DNA damage and repair
Abstract Mutations arise when DNA lesions escape DNA repair. To delineate the contributions of DNA damage and DNA repair deficiency to mutagenesis we sequenced 2,717 genomes of wild-type and 53 DNA repair defective C. elegans strains propagated through several generations or exposed to 11 genotoxins at multiple doses. Combining genotoxin exposure and DNA repair deficiency alters mutation rates or leads to unexpected mutation spectra in nearly 40% of all experimental conditions involving 9/11 of genotoxins tested and 32/53 genotypes. For 8/11 genotoxins, signatures change in response to more than one DNA repair deficiency, indicating that multiple genes and pathways are involved in repairing DNA lesions induced by one genotoxin. For many genotoxins, the majority of observed single nucleotide variants results from error-prone translesion synthesis, rather than primary mutagenicity of altered nucleotides. Nucleotide excision repair mends the vast majority of genotoxic lesions, preventing up to 99% of mutations. Analogous mutagenic DNA damage-repair interactions can also be found in cancers, but, except for rare cases, effects are weak owing to the unknown histories of genotoxic exposures and DNA repair status. Overall, our data underscore that mutation spectra are joint products of DNA damage and DNA repair and imply that mutational signatures computationally derived from cancer genomes are more variable than currently anticipated.
Volkova Nadezda V、Meier Bettina、Bertolini Simone、Abascal Federico、Gerstung Moritz、Voeringer Harald、Martincorena I?igo、Campbell Peter J、Gonz¨￠lez-Huici V¨actor、Gartner Anton、Gonzalez Santiago
European Molecular Biology Laboratory, European Bioinformatics InstituteCentre for Gene Regulation and Expression, University of DundeeCentre for Gene Regulation and Expression, University of DundeeCancer, Ageing and Somatic Mutation, Wellcome Sanger InstituteEuropean Molecular Biology Laboratory, European Bioinformatics Institute||European Molecular Biology Laboratory, Genome Biology UnitEuropean Molecular Biology Laboratory, European Bioinformatics InstituteCancer, Ageing and Somatic Mutation, Wellcome Sanger InstituteCancer, Ageing and Somatic Mutation, Wellcome Sanger Institute||Department of Haematology, University of Cambridge||Department of Haematology, Addenbrooke?ˉs HospitalCentre for Gene Regulation and Expression, University of Dundee||Institute for Research in Biomedicine (IRB Barcelona), Parc Cient¨afic de BarcelonaCentre for Gene Regulation and Expression, University of Dundee||Center for Genomic Integrity, Institute for Basic Science||Department of Biological Sciences, School of Life Sciences, Ulsan National Institute of Science and TechnologyEuropean Molecular Biology Laboratory, European Bioinformatics Institute||Institute for Research in Biomedicine (IRB Barcelona), Parc Cient¨afic de Barcelona
基础医学生物科学研究方法、生物科学研究技术遗传学
Volkova Nadezda V,Meier Bettina,Bertolini Simone,Abascal Federico,Gerstung Moritz,Voeringer Harald,Martincorena I?igo,Campbell Peter J,Gonz¨￠lez-Huici V¨actor,Gartner Anton,Gonzalez Santiago.Mutational signatures are jointly shaped by DNA damage and repair[EB/OL].(2025-03-28)[2025-06-22].https://www.biorxiv.org/content/10.1101/686295.点此复制
评论