Signatures of TOP1 transcription-associated mutagenesis in cancer and germline

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.

Accurate and sensitive mutational signature analysis with MuSiCal

“…11e). Interestingly, our updated MuSiCal version of ID4 is very similar to the experimentally derived signature of topoisomerase 1 (TOP1)-mediated deletions in RNase-H2-null cells, predominantly consisting of 2-bp deletions at short tandem repeats (STRs) with 2 or 3 repeat units, as well as 2-bp deletions with 1-bp MH [58] (Extended Data Fig. 11f).…”

“…ID signatures can provide unique information on both endogenous and exogenous mutagenic processes, but they have been under-studied until recently, in part due to the relatively low mutational burden of IDs compared to SBSs [14, 16, 18, 58–60]. Our reanalysis results in a substantial revision and expansion of the COSMIC catalog of ID signatures.…”

“…Application of MuSiCal to alternative signature definitions should further disentangle mutational processes and help gain insights into signatures with unknown etiologies. In particular, the standard definition of ID signatures with 83 channels lacks more detailed indel characteristics, such as affected nucleotides of > 1-bp indels and nucleotide context of flanking sequences beyond repetitive and microhomology information (e.g., the specific motif as observed for TOP1 signature [58]). As a result, some of the ID signatures may correspond to multiple mutational processes.…”

“…The reconstructed signature has cosine similarity of 0.996 with COSMIC ID4 and is shown at the very bottom. f. The TOP1-associated ID spectrum observed in RNase-H2-null cells from [58] (top) is compared to the reconstructed spectra using the COSMIC (middle) and the MuSiCal catalog (bottom). The MuSiCal catalog better reconstructs the experimentally derived TOP1 signature.…”

Mutational topography reflects clinical neuroblastoma heterogeneity

“…x 10 -5 ). ID4, a signature enriched for deletions (>1 bp) at repeats and microhomology, recently associated with TOP1 mutational activity in cancer and healthy cells 31 , on the other hand, was significantly more prevalent in non-high-risk patients (P < 1.3 x 10 -3 ). ID4 displayed an association with SBS40 and high anticorrelation with all the other indel signatures, notably with the ones related to SBS3 (ID6, ID8, ID9) or SBS18 (ID1, ID2).…”