Structure-driven effects on genomic DNA damage propensity at G-quadruplex sites

Abstract

Our genome contains about half a million sites capable of forming G-quadruplex (G4) structures. Such structural formations, often localised at important regulatory loci, have high capability of altering the predisposition of corresponding genomic spans to endogenous and exogenous DNA damage. In this work, we devised an approach to systematically enrich and zoom onto structure-driven effects on the propensity to undergo 9 types of DNA damage: ultraviolet radiation-induced pyrimidine-pyrimidone (6-4) photoproduct PP and cyclobutane pyrimidine dimer CPD couplings (two dyad-based subtypes in each), cisplatin-mediated G-G crosslinks, reactive oxygen species induced 8-oxoguanine damage, DNA fragmentation upon natural decay and fossilisation, breakages from artificial enzymatic cleavage and ultrasound sonication. Our results indicate that the structural effects on DNA damageability at G4 sites are not a simple combination of shielding (G4 strand) and de-shielding (opposite strand) against damaging factors, and the outcomes have different patterns and variation from one damage type to another, highly dependent on the G4 strength and relative strand localisation. The results are accompanied by electronic structure calculations, detailed structural parallels and considerations. Graphical Abstract. An illustration of the considered damage factors acting on G-quadruplex sites, through strand-specific (two pointing thunder signs) and strand-invariant (a single pointing thunder sign) manner. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=151 SRC="FIGDIR/small/471014v1_ufig1.gif" ALT="Figure 1"> View larger version (28K): org.highwire.dtl.DTLVardef@91e464org.highwire.dtl.DTLVardef@296bc8org.highwire.dtl.DTLVardef@1635413org.highwire.dtl.DTLVardef@24b86a_HPS_FORMAT_FIGEXP M_FIG C_FIG