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Strand-resolved mutagenicity of DNA damage and repair

View ORCID ProfileCraig J. Anderson, View ORCID ProfileLana Talmane, View ORCID ProfileJuliet Luft, View ORCID ProfileMichael D. Nicholson, View ORCID ProfileJohn Connelly, View ORCID ProfileOriol Pich, Susan Campbell, View ORCID ProfileVasavi Sundaram, Frances Connor, View ORCID ProfilePaul A. Ginno, Liver Cancer Evolution Consortium, View ORCID ProfileNúria López-Bigas, View ORCID ProfilePaul Flicek, View ORCID ProfileColin A. Semple, View ORCID ProfileDuncan T. Odom, View ORCID ProfileSarah J. Aitken, View ORCID ProfileMartin S. Taylor
doi: https://doi.org/10.1101/2022.06.10.495644
Craig J. Anderson
1Medical Research Council Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK
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Lana Talmane
1Medical Research Council Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK
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Juliet Luft
1Medical Research Council Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK
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Michael D. Nicholson
2Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK
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John Connelly
1Medical Research Council Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK
3Medical Research Council Toxicology Unit, University of Cambridge, Cambridge, UK
4Edinburgh Pathology, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK
5Laboratory Medicine, NHS Lothian, Edinburgh, UK
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Oriol Pich
6Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona, Spain
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Susan Campbell
1Medical Research Council Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK
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Vasavi Sundaram
7European Molecular Biology Laboratory, European Bioinformatics Institute, Hinxton, UK
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Frances Connor
8Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, UK
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Paul A. Ginno
9German Cancer Research Center (DKFZ), Heidelberg, Germany
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Núria López-Bigas
6Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona, Spain
10Universitat Pompeu Fabra (UPF), Barcelona, Spain
11Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain
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Paul Flicek
7European Molecular Biology Laboratory, European Bioinformatics Institute, Hinxton, UK
8Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, UK
12Department of Genetics, University of Cambridge, Cambridge, UK
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Colin A. Semple
1Medical Research Council Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK
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Duncan T. Odom
8Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, UK
9German Cancer Research Center (DKFZ), Heidelberg, Germany
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  • For correspondence: d.odom@dkfz-heidelberg.de sa696@cam.ac.uk martin.taylor@ed.ac.uk
Sarah J. Aitken
3Medical Research Council Toxicology Unit, University of Cambridge, Cambridge, UK
8Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, UK
13Department of Pathology, University of Cambridge, Cambridge, UK
14Department of Histopathology, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK
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  • For correspondence: d.odom@dkfz-heidelberg.de sa696@cam.ac.uk martin.taylor@ed.ac.uk
Martin S. Taylor
1Medical Research Council Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK
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  • ORCID record for Martin S. Taylor
  • For correspondence: d.odom@dkfz-heidelberg.de sa696@cam.ac.uk martin.taylor@ed.ac.uk
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Summary

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 DNA adducts, 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 adducts5. We find that DNA damage tolerance is also common during transcription, where RNA-polymerases frequently bypass lesions without triggering repair. At multiple genomic scales, we show the pattern of DNA damage induced mutations is 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 corrupt the fidelity of nucleotide excision repair and actively drive oncogenic mutagenesis. These results provide insight into how strand-asymmetric mechanisms underlie the formation, tolerance, and repair of DNA damage, thereby shaping cancer genome evolution.

Competing Interest Statement

P.F. is a member of the Scientific Advisory Boards of Fabric Genomics, Inc. and Eagle Genomics, Ltd. The other authors declare no competing interests.

Footnotes

  • ↵15 Liver Cancer Evolution Consortium

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license.
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Strand-resolved mutagenicity of DNA damage and repair
Craig J. Anderson, Lana Talmane, Juliet Luft, Michael D. Nicholson, John Connelly, Oriol Pich, Susan Campbell, Vasavi Sundaram, Frances Connor, Paul A. Ginno, Liver Cancer Evolution Consortium, Núria López-Bigas, Paul Flicek, Colin A. Semple, Duncan T. Odom, Sarah J. Aitken, Martin S. Taylor
bioRxiv 2022.06.10.495644; doi: https://doi.org/10.1101/2022.06.10.495644
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Strand-resolved mutagenicity of DNA damage and repair
Craig J. Anderson, Lana Talmane, Juliet Luft, Michael D. Nicholson, John Connelly, Oriol Pich, Susan Campbell, Vasavi Sundaram, Frances Connor, Paul A. Ginno, Liver Cancer Evolution Consortium, Núria López-Bigas, Paul Flicek, Colin A. Semple, Duncan T. Odom, Sarah J. Aitken, Martin S. Taylor
bioRxiv 2022.06.10.495644; doi: https://doi.org/10.1101/2022.06.10.495644

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