Analysis of gene expression and mutation data points on contribution of transcription to the mutagenesis by APOBEC enzymes

Since the discovery of the role of the APOBEC enzymes in human cancers, the mechanisms of this type of mutagenesis remain little understood. Theoretically, targeting of single-stranded DNA by the APOBEC enzymes could occur during cellular processes leading to the unwinding of DNA double-stranded structure. Some evidence points to the importance of replication in the APOBEC mutagenesis, while the role of transcription is still underexplored. Here, we analyzed gene expression and whole genome sequencing data from five types of human cancers with substantial APOBEC activity to estimate the involvement of transcription in the APOBEC mutagenesis and compare its impact with that of replication. Using the TCN motif as the mutation signature of the APOBEC enzymes, we observed a correlation of active APOBEC mutagenesis with gene expression, confirmed the increase of APOBEC-induced mutations in early-replicating regions and estimated the relative impact of transcription and replication on the APOBEC mutagenesis. We also found that the known effect of higher density of APOBEC-induced mutations on the lagging strand was highest in middle-replicating regions and observed higher APOBEC mutation density on the sense strand, the latter bias positively correlated with the gene expression level.

Automated summary

The mechanisms of APOBEC mutagenesis in human cancers remain poorly understood, with evidence suggesting the importance of replication and the underexplored role of transcription. Gene expression and whole genome sequencing data from five types of human cancers with significant APOBEC activity were analyzed to estimate the involvement of transcription, compare its impact with that of replication, and explore the relative effects on APOBEC mutagenesis. Active APOBEC mutagenesis was found to correlate with gene expression, with an increase in APOBEC-induced mutations in early-replicating regions, and a higher APOBEC mutation density positively correlated with gene expression levels.