Peer-Reviewed Journal Details
Mandatory Fields
Terzidis, MA;Prisecaru, A;Molphy, Z;Barron, N;Randazzo, A;Dumont, E;Krokidis, MG;Kellett, A;Chatgilialoglu, C
2016
January
Free Radical Research
Radical-induced purine lesion formation is dependent on DNA helical topology
Published
6 ()
Optional Fields
G-QUADRUPLEX HUMAN-CELLS REPAIR QUANTIFICATION GUANINE OXYGEN DAMAGE
50
91
101
Herein we report the quantification of purine lesions arising from gamma-radiation sourced hydroxyl radicals (HO center dot) on tertiary dsDNA helical forms of supercoiled (SC), open circular (OC), and linear (L) conformation, along with single-stranded folded and non-folded sequences of guanine-rich DNA in selected G-quadruplex structures. We identify that DNA helical topology and folding plays major, and unexpected, roles in the formation of 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxo-dG) and 8-oxo-7,8-dihydro-2'-deoxyadenosine (8-oxo-dA), along with tandem-type purine lesions 50,8-cyclo-20-deoxyguanosine (50,8-cdG) and 50,8-cyclo-20-deoxyadenosine (50,8-cdA). SC, OC, and L dsDNA conformers together with folded and non-folded G-quadruplexes d[TGGGGT](4) (TG4T), d[AGGG(TTAGGG)(3)] (Tel22), and the mutated tel24 d[TTGGG(TTAGGG)(3)A] (mutTel24) were exposed to HO center dot radicals and purine lesions were then quantified via stable isotope dilution LC-MS/MS analysis. Purine oxidation in dsDNA follows L> OC >> SC indicating greater damage towards the extended B-DNA topology. Conversely, G-quadruplex sequences were significantly more resistant toward purine oxidation in their unfolded states as compared with G-tetrad folded topologies; this effect is confirmed upon comparative analysis of Tel22 (similar to 50% solution folded) and mutTel24 (similar to 90% solution folded). In an effort to identify the accessibly of hydroxyl radicals to quadruplex purine nucleobases, G-quadruplex solvent cavities were then modeled at 1.33 angstrom with evidence suggesting that folded G-tetrads may act as potential oxidant traps to protect against chromosomal DNA damage.
ABINGDON
1071-5762
10.1080/10715762.2016.1244820
Grant Details