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

Abstract

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.

An APOBEC3 Mutational Signature in the Genomes of Human-Infecting Orthopoxviruses

“…Whereas experimental analyses will be necessary to determine the source of APOBEC3-mediated editing in hMPXV1 genomes and the nature of repair mechanisms (or lack thereof), we found that mutations are more common in highly expressed genes. A similar observation was recently reported for some cancer genomes ( 11 ), explained by the fact that transcription leads to dsDNA unwinding, with the transient formation of single-stranded DNA (ssDNA) regions, a target of APOBEC3-mediated editing. The same authors also reported transcriptional asymmetry of APOBEC3 mutation signatures, a feature we do not observe in hMPXV1 genes.…”

“…APOBEC3 proteins have been intensely investigated for their mutagenic role in human cancers. In cancer genomes, there is contrasting evidence for transcriptional asymmetry of APOBEC3-induced mutations ( 10 – 12 ). Replication asymmetry is instead observed, with most mutations occurring on the lagging strand ( 10 – 12 ).…”

“…In cancer genomes, there is contrasting evidence for transcriptional asymmetry of APOBEC3-induced mutations ( 10 – 12 ). Replication asymmetry is instead observed, with most mutations occurring on the lagging strand ( 10 – 12 ). Conversely, APOBEC3 editing of human papillomavirus and of plasmid DNA instead occurs on both strands ( 13 , 14 ).…”

“…The same authors also reported transcriptional asymmetry of APOBEC3 mutation signatures, a feature we do not observe in hMPXV1 genes. However, both the association with transcription levels and transcription asymmetry are still controversial findings in human cancer genomes ( 10 – 12 , 36 , 37 ). Thus, experimental analyses will be required to determine the molecular mechanisms of APOBEC3-mediated editing of hMPXV1 genomes and the role of transcription.…”

APOBEC mutagenesis is low in most types of non-B DNA structures

“…Several types of mutational heterogeneity along the genome, presumably associated with replication and transcription ( Haradhvala et al., 2016 ), were identified for APOBEC mutagenesis. An increased density of APOBEC-induced mutations was found in early-replicating genome regions ( Kazanov et al., 2015 ), as opposed to other types of cancer mutagenesis, and in highly transcribed genes ( Chervova et al., 2021 ). Higher rate of APOBEC-induced mutations was also observed on the lagging replicating DNA strand ( Seplyarskiy et al., 2016 ) and the non-transcribed DNA strand ( Chervova et al., 2021 ).…”