Signatures of TOP1 transcription-associated mutagenesis in cancer and germline

Martin A. M. Reijns (), David A. Parry, Thomas C. Williams, Ferran Nadeu, Rebecca L. Hindshaw, Diana O. Rios Szwed, Michael D. Nicholson, Paula Carroll, Shelagh Boyle, Romina Royo, Alex J. Cornish, Hang Xiang, Kate Ridout, Anna Schuh, Konrad Aden, Claire Palles, Elias Campo, Tatjana Stankovic, Martin S. Taylor () and Andrew P. Jackson ()
Additional contact information
Martin A. M. Reijns: The University of Edinburgh
David A. Parry: The University of Edinburgh
Thomas C. Williams: The University of Edinburgh
Ferran Nadeu: Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS)
Rebecca L. Hindshaw: Institute of Cancer and Genomic Sciences, University of Birmingham
Diana O. Rios Szwed: The University of Edinburgh
Michael D. Nicholson: The University of Edinburgh
Paula Carroll: The University of Edinburgh
Shelagh Boyle: The University of Edinburgh
Romina Royo: Barcelona Supercomputing Center (BSC)
Alex J. Cornish: The Institute of Cancer Research
Hang Xiang: Institute of Clinical Molecular Biology, Christian-Albrechts-University and University Hospital Schleswig-Holstein
Kate Ridout: University of Oxford
Anna Schuh: University of Oxford
Konrad Aden: Institute of Clinical Molecular Biology, Christian-Albrechts-University and University Hospital Schleswig-Holstein
Claire Palles: Institute of Cancer and Genomic Sciences, University of Birmingham
Elias Campo: Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS)
Tatjana Stankovic: Institute of Cancer and Genomic Sciences, University of Birmingham
Martin S. Taylor: The University of Edinburgh
Andrew P. Jackson: The University of Edinburgh

Nature, 2022, vol. 602, issue 7898, 623-631

Abstract: Abstract The mutational landscape is shaped by many processes. Genic regions are vulnerable to mutation but are preferentially protected by transcription-coupled repair1. In microorganisms, transcription has been demonstrated to be mutagenic2,3; however, the impact of transcription-associated mutagenesis remains to be established in higher eukaryotes4. Here we show that ID4—a cancer insertion–deletion (indel) mutation signature of unknown aetiology5 characterized by short (2 to 5 base pair) deletions —is due to a transcription-associated mutagenesis process. We demonstrate that defective ribonucleotide excision repair in mammals is associated with the ID4 signature, with mutations occurring at a TNT sequence motif, implicating topoisomerase 1 (TOP1) activity at sites of genome-embedded ribonucleotides as a mechanistic basis. Such TOP1-mediated deletions occur somatically in cancer, and the ID-TOP1 signature is also found in physiological settings, contributing to genic de novo indel mutations in the germline. Thus, although topoisomerases protect against genome instability by relieving topological stress6, their activity may also be an important source of mutations in the human genome.

Date: 2022
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DOI: 10.1038/s41586-022-04403-y

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