Signatures of TOP1 transcription-associated mutagenesis in cancer and germline

Journal article

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 mutagenic^2,3; 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.

Authors: Reijns, MAM; Parry, DA; Williams, TC; Nadeu, F; Hindshaw, RL

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: Nature Research
• Journal: Nature
• Volume: 602
• Issue: 7898
• Pages: 623-631
• Publication date: 2022-02-09
• DOI: 10.1038/s41586-022-04403-y
• EISSN: 1476-4687
• ISSN: 0028-0836
• Language: English
• Keywords: Transcription factor; Biology; Transcription (linguistics); Gene; Mutation; Germline mutation; Genetics; Germline; Computational biology; Mutagenesis