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

While somatic mutations are known to be enriched in genome regions with non -canonical DNA secondary structure, the impact of particular mutagens still needs to be elucidated. Here, we demonstrate that in human cancers, the APOBEC mutagenesis is not enriched in direct repeats, mirror repeats, short tandem re-peats, and G-quadruplexes, and even decreased below its level in B-DNA for can-cer samples with very high APOBEC activity. In contrast, we observe that the APOBEC-induced mutational density is positively associated with APOBEC activ-ity in inverted repeats (cruciform structures), where the impact of cytosine at the 3'-end of the hairpin loop is substantial. Surprisingly, the APOBEC-signature mu-tation density per TC motif in the single-stranded DNA of a G-quadruplex (G4) is lower than in the four-stranded part of G4 and in B-DNA. The APOBEC mutagen-esis, as well as the UV-mutagenesis in melanoma samples, are absent in Z-DNA re-gions, owing to the depletion of their mutational signature motifs.

Automated summary

In human cancers, APOBEC mutagenesis is not enriched in certain DNA secondary structures and is positively associated with inverted repeats. The APOBEC-induced mutational density is lower in G-quadruplex compared to four-stranded G-quadruplex and B-DNA. UV and APOBEC mutagenesis are absent in Z-DNA regions.