Noncanonical secondary structures arising from non-B DNA motifs are determinants of mutagenesis

Abstract

Somatic mutations show variation in density across cancer genomes. Previous studies have shown that chromatin organization and replication time domains are correlated with, and thus predictive of, this variation. Here, we analyze 1809 whole-genome sequences from 10 cancer types to show that a subset of repetitive DNA sequences, called non-B motifs that predict noncanonical secondary structure formation can independently account for variation in mutation density. Combined with epigenetic factors and replication timing, the variance explained can be improved to 43%-76%. Approximately twofold mutation enrichment is observed directly within non-B motifs, is focused on exposed structural components, and is dependent on physical properties that are optimal for secondary structure formation. Therefore, there is mounting evidence that secondary structures arising from non-B motifs are not simply associated with increased mutation density-they are possibly causally implicated. Our results suggest that they are determinants of mutagenesis and increase the likelihood of recurrent mutations in the genome. This analysis calls for caution in the interpretation of recurrent mutations and highlights the importance of taking non-B motifs that can simply be inferred from the reference sequence into consideration in background models of mutability henceforth.

Alternative splicing modulation by G-quadruplexes

“…Non-B DNA motifs. Identification of each non-B DNA motif was performed using the genomewide maps in humans and mice provided by (Cer et al 2013) and processed as described in (Georgakopoulos-Soares et al 2018). We focused on seven non-B DNA motifs; inverted repeats, mirror repeats, H-DNA which forms at a subset of mirror repeats with high AG content, G4s, Z-DNA which forms at non-AT alternating purine pyrimidine stretches, short tandem repeats and direct repeats (Fig 1a), (S3).…”

“…Similarly, a G4 in the promoter of the proto-oncogene KRAS has a negative effect on expression levels (Cogoi & Xodo 2006). Moreover, G4s are also implicated in genomic instability in cancer and neurodegenerative diseases (Siddiqui-Jain et al 2002), (Wu & Brosh 2010), (De & Michor 2011), (Simone et al 2015), (Georgakopoulos-Soares et al 2018).…”

Hoogsteen base pairs increase the susceptibility of double-stranded DNA to cytotoxic damage

“…For example, Hoogsteen bps have already been proposed to grant formaldehyde access to neighboring G-C Watson-Crick bps resulting in the hydroxymethylation of the cytosine amino nitrogen in dsDNA (85). Beyond Hoogsteen bps in dsDNA, other non-B DNA motifs have also been linked to mutagenesis that could expose Watson-Crick faces of nucleotide bases (86). Further studies are needed to understand how sequence-specific DNA dynamics may contribute to damage.…”

In-depth Bioinformatic Analyses of Human SARS-CoV-2, SARS-CoV, MERS-CoV, and OtherNidoviralesSuggest Important Roles of Noncanonical Nucleic Acid Structures in Their Lifecycles

“…and stability of resulting secondary structure is not simple. While some authors believe that longer IRs are more stable, others suggest that there is an energy optimum defined by arm and spacer length (Sinden et al, 1991;Brázda et al, 2016;Georgakopoulos-Soares et al, 2018). This is a provisional file, not the final typeset article FIGURE 5 | Differences in IR frequency by annotated locus.…”