Electron attachment-induced DNA single-strand breaks at the pyrimidine sites.
To elucidate the contribution of pyrimidine in DNA strand breaks caused by low-energy electrons (LEEs), theoretical investigations of the LEE attachment-induced C(3')-O(3'), and C(5')-O(5') σ bond as well as N-glycosidic bond breaking of 2'-deoxycytidine-3',5'-diphosphate and 2'-deoxythymidine-3',5'-diphosphate were performed using the B3LYP/DZP++ approach. The base-centered radical anions are electronically stable enough to assure that either the C-O or glycosidic bond breaking processes might compete with the electron detachment and yield corresponding radical fragments and anions. In the gas phase, the computed glycosidic bond breaking activation energy (24.1 kcal/mol) excludes the base release pathway. The low-energy barrier for the C(3')-O(3') σ bond cleavage process (∼6.0 kcal/mol for both cytidine and thymidine) suggests that this reaction pathway is the most favorable one as compared to other possible pathways. On the other hand, the relatively low activation energy barrier (∼14 kcal/mol) for the C(5')-O(5') σ bond cleavage process indicates that this bond breaking pathway could be possible, especially when the incident electrons have relatively high energy (a few electronvolts). The presence of the polarizable medium greatly increases the activation energies of either C-O σ bond cleavage processes or the N-glycosidic bond breaking process. The only possible pathway that dominates the LEE-induced DNA single strands in the presence of the polarizable surroundings (such as in an aqueous solution) is the C(3')-O(3') σ bond cleavage (the relatively low activation energy barrier, ∼13.4 kcal/mol, has been predicted through a polarizable continuum model investigation). The qualitative agreement between the ratio for the bond breaks of C(5')-O(5'), C(3')-O(3') and N-glycosidic bonds observed in the experiment of oligonucleotide tetramer CGAT and the theoretical sequence of the bond breaking reaction pathways have been found. This consistency between the theoretical predictions and the experimental observations provides strong supportive evidences for the base-centered radical anion mechanism of the LEE-induced single-strand bond breaking around the pyrimidine sites of the DNA single strands.
Gu
Jiande
J
Drug Design & Discovery Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Shanghai Institutes for Biological Sciences, CAS, Shanghai 201203 PR China. jiandegush@go.com
Wang
Jing
J
Leszczynski
Jerzy
J
D002244:Carbon / Q000737:chemistry; D053904:DNA Breaks, Single-Stranded; D003845:Deoxycytosine Nucleotides / Q000737:chemistry*; D004583:Electrons; D006027:Glycosides / Q000737:chemistry; D008958:Models, Molecular; D010100:Oxygen / Q000737:chemistry; D013942:Thymine Nucleotides / Q000737:chemistry*
C523305:2'-deoxythymidine-3',5'-diphosphate; D003845:Deoxycytosine Nucleotides; D006027:Glycosides; D013942:Thymine Nucleotides; C059281:2'-deoxycytidine 3',5'-diphosphate; D002244:Carbon; D010100:Oxygen