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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.

Signatures of TOP1 transcription-associated mutagenesis in cancer and germline