한빛사 논문
University of Dundee, 기초과학연구원, Ulsan National Institute of Science and Technology(UNIST)
Nadezda V. Volkova1,10, Bettina Meier2,10, Víctor González-Huici2,9,10, Simone Bertolini2, Santiago Gonzalez1,9, Harald Vöhringer1, Federico Abascal3, Iñigo Martincorena3, Peter J. Campbell3,4,5, Anton Gartner2,6,7,* & Moritz Gerstung1,8,*
1European Molecular Biology Laboratory, European Bioinformatics Institute (EMBL-EBI), Hinxton CB10 1SD, UK. 2Centre for Gene Regulation and Expression, University of Dundee, Dundee DD1 5EH, Scotland. 3Cancer, Ageing and Somatic Mutation, Wellcome Sanger Institute, Hinxton CB10 1SA, UK. 4Department of Haematology, University of Cambridge, Cambridge CB2 0XY, UK. 5Department of Haematology, Addenbrooke’s Hospital, Cambridge CB2 0QQ, UK. 6Center for Genomic Integrity, Institute for Basic Science, Ulsan 689-798, Republic of Korea. 7Department of Biological Sciences, School of Life Sciences, Ulsan National Institute of Science and Technology, Ulsan 689-798, Republic of Korea. 8European Molecular Biology Laboratory, Genome Biology Unit, 69177 Heidelberg, Germany. 9Present address: Institute for Research in Biomedicine (IRB Barcelona), Parc Científic de Barcelona, 08028 Barcelona, Spain. 10These authors contributed equally: Nadezda V. Volkova, Bettina Meier, Víctor González-Huici.
*Corresponding authors
Abstract
Cells possess an armamentarium of DNA repair pathways to counter DNA damage and prevent mutation. Here we use C. elegans whole genome sequencing to systematically quantify the contributions of these factors to mutational signatures. We analyse 2,717 genomes from wild-type and 53 DNA repair defective backgrounds, exposed to 11 genotoxins, including UV-B and ionizing radiation, alkylating compounds, aristolochic acid, aflatoxin B1, and cisplatin. Combined genotoxic exposure and DNA repair deficiency alters mutation rates or signatures in 41% of experiments, revealing how different DNA alterations induced by the same genotoxin are mended by separate repair pathways. Error-prone translesion synthesis causes the majority of genotoxin-induced base substitutions, but averts larger deletions. Nucleotide excision repair prevents up to 99% of point mutations, almost uniformly across the mutation spectrum. Our data show that mutational signatures are joint products of DNA damage and repair and suggest that multiple factors underlie signatures observed in cancer genomes.
논문정보
관련 링크
관련분야 연구자보기
관련분야 논문보기
해당논문 저자보기