Fig. 4: RER-deficient tumours have an ID4 signature associated with transcription and a TNT sequence motif.

a, ID4 contributes substantially to the mutational spectrum of Rnaseh2b-KO mouse intestinal tumours (WGS, paired tumour–normal samples from n = 6 mice). b, ID4 contribution is greater in transcribed regions of the genome. Statistical analysis was performed using a two-sided Fisher’s exact test, comparing ID4 versus other indels. n = 969 indels from 6 biologically independent tumours. c, 2 bp STR/SNMH deletions have biased sequence composition. Genome, frequency of dinucleotides in STR/SNMH sequences in the mappable genome. Deletions are right aligned and indicated by bold red font. d, e, A TNT sequence motif is present at all 2 bp STR and SNMH deletions. d, Sequence logo: two-bit representation of the sequence context of 2 bp deletions at STR and SNMH sequences. e, Deletion sites are significantly enriched for the TNT sequence motif compared with genome-wide occurrence, for all genome sequences, as well as STR and SNMH sites. Statistical analysis was performed using two-sided Fisher’s exact tests, comparing observed versus expected. n = 228 (all, P = 1.7 × 10⁻²⁸), n = 124 (STR, P = 0.0008), n = 77 (SNMH, P = 1.4 × 10⁻⁸) deletions in 6 biologically independent tumours. f, Model for TOP1-mediated mutations at TNT sequences containing embedded ribonucleotides, in which strand realignment results in a two-nucleotide deletion (see main text). nt, nucleotide.