Signatures of TOP1 transcription-associated mutagenesis in cancer and germline
Martin A.M. Reijns, David Parry, Thomas Williams, Ferran Nadeu, Rebecca L. Hindshaw, Diana O. Rios Szwed, Michael D. Nicholson, Paula Carroll, Shelagh Boyle, Romina Royo, Alex J. Cornish, Xiang Hang, Kate Ridout, John C. Ambrose, Prabhu Arumugam, R. Bevers, Marta Bleda, Freya Boardman-Pretty, C. R. Boustred, Helen Brittain, Mark J. Caulfield, G. C. Chan, Greg Elgar, Tom Fowler, Adam Giess, Angela Hamblin, Shirley Henderson, Tim Hubbard, R. Jackson, J. Louise Jones, Dalia Kasperavičiūtė, Melis Kayikci, Athanasios Kousathanas, L. Lahnstein, S. E. A. Leigh, I. U. S. Leong, Javier Ferreiros, F. Maleady-Crowe, Meriel McEntagart, Federico Minneci, Loukas Moutsianas, Michael Mueller, Nirupa Murugaesu, Anna C. Need, Peter O’Donovan, Chris A. Odhams, Christine Patch, Mariana Buongermino Pereira, D. Perez-Gil, J. Pullinger, T. Rahim, Augusto Rendon, Tim Rogers, K. Savage, Kushmita Sawant, Richard H. Scott, Afshan Siddiq, A. Sieghart, Samuel C. Smith, Alona Sosinsky, Alexander Stuckey, M. Tanguy, Ana Lisa Taylor Tavares, Ellen Thomas, Simon R. Thompson, Arianna Tucci, M. J. Welland, Eleanor Williams, Katarzyna Witkowska, S. M. Wood, Colorectal Cancer Domain UK 100,000 Genomes Project, Daniel Chubb, Alex J. Cornish, Ben Kinnersley, Richard S. Houlston, David C. Wedge, Andreas Gruber, Anna Frangou, William Cross, Trevor A. Graham, Andrea Sottoriva, Giulio Caravagna, Núria López-Bigas, Claudia Arnedo-Pac, David N. Church, Richard Culliford, S. Thorn, Philip Quirke, Henry M. Wood, Ian Tomlinson, Boris Noyvert, Anna Schuh, Konrad Aden, Claire Palles, Elı́as Campo, Tatjana Stanković, Martin S. Taylor, Andrew P. Jackson
Abstract
Abstract The mutational landscape is shaped by many processes. Genic regions are vulnerable to mutation but are preferentially protected by transcription-coupled repair 1 . In microorganisms, transcription has been demonstrated to be mutagenic 2,3 ; however, the impact of transcription-associated mutagenesis remains to be established in higher eukaryotes 4 . Here we show that ID4—a cancer insertion–deletion (indel) mutation signature of unknown aetiology 5 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 stress 6 , their activity may also be an important source of mutations in the human genome.