APOBEC mutagenesis is low in most types of non-B DNA structures, unlike other types of cancer mutagenesis

Abstract

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 repeats, and G-quadruplexes, and even decreased below its level in B-DNA for cancer samples with very high APOBEC activity. In contrast, we observe that the APOBEC-induced mutational density is positively associated with APOBEC activity in inverted repeats (cruciform structures), where the impact of cytosine at the 3'-end of the hairpin loop is substantial. Surprisingly, the APOBEC-signature mutation 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 mutagenesis, as well as the UV-mutagenesis in melanoma samples are absent in Z-DNA regions, due to depletion of their mutational signature motifs.

RNA transcripts suppress G-quadruplex structures through G-loop formation

“…Replacement of this strand could therefore be important to maintain genome integrity. In line with this, the mutation frequency in the displaced non-G4 strand is sustained low despite enrichment of cytosine deaminase target motifs 29 . Second, it could be important for maintaining accessible chromatin at actively transcribed genes by erasing DNA methylations and removing nucleosomes (Figure S7b).…”