How abasic sites impact hole transfer dynamics in GC-rich DNA sequences

Abstract

Changes in DNA charge transfer properties upon the creation of apurinic and apyrimidinic sites have been used to monitor DNA repair processes, given that such lesions generally reduce charge transfer yields. However, because these lesions translate into distinct intra and extrahelical conformations depending on the nature of the unpaired base and its DNA context, it is unclear the actual impact of such diverse conformations on charge transfer. Here we combine classical molecular dynamics, quantum/molecular mechanics (QM/MM) calculations, and kinetic Monte Carlo simulations to investigate the impact of abasic sites on the structure and hole transfer (HT) properties of DNA. We consider both apurinic and apyrimidinic sites in polyG and polyGC sequences and find that most situations lead to intrahelical conformations where HT rates are significantly slowed down due to the energetic disorder induced by the abasic void. In contrast, the presence of an unpaired C flanked by C bases leads to an extrahelical conformation where stacking among G sites is reduced, leading to an attenuation of electronic couplings and a destabilization of hole states. Interestingly, this leads to an asymmetric HT behavior, given that the 5' to 3' transfer along the G strand is slowed down by one order of magnitude while the opposite 3' to 5' transfer remains similar to that estimated for the reference polyG sequence. Our simulations thus suggest that electrochemical monitoring of the DNA repair process following changes in charge transfer properties can miss repair events linked to abasic sites adopting extrahelical conformations.

Tandem Substitutions in Somatic Hypermutation

“…Additionally, UNG creates ~45°k inks at dUTP positions (61), which facilitate the extrusion and subsequent skipping of the abasic site by a DNA damage tolerant DNA polymerase. Considering the polydypirimidine motifs, such extruded positioning could be facilitated by the relatively small flanking pyrimidine bases, in a similar fashion as was recently described for flanking cytosine bases (62). Indeed, mismatched pairs have an increased propensity for spontaneous base flipping (63), and the presence of UNG further increases the lifetime of open states following spontaneous base-pair dissociation and twists the unstacked nucleotides out of their helical conformation (64)(65)(66).…”

“…Although AP sites, mismatched bases, and uracil residues have a particular proclivity to adopt extruded configurations (62,63,(67)(68)(69), juxtalocations could theoretically also result from spontaneous base flipping of matched base pairs, especially A-T pairs (66). Indeed, we observe that germline motifs AT and TA, which contain no cytosine bases on either strand and would therefore remain unexplained through the UNG pathway, are the least abundant reference motifs of all tandem substitutions -yet are not absent.…”

Walking around Ribosomal Small Subunit: A Possible “Tourist Map” for Electron Holes

“…Accordingly, charge transport in RNA can significantly differ from that in DNA and is worth thorough investigation. However, while multiple theoretical and experimental studies addressed charge transport in DNA [16][17][18][19], such studies for RNA [14,20,21] are rare. Very recently, it was shown that charge transport along the DNA molecule plays an important role in regulation of the replication process [18] and DNA repair [19], and disruption of DNA conductivity may cause severe diseases [22].…”

Walking Around Ribosomal Small Subunit: A Possible “Tourist Map” for an Electron Hole

“…tRNA and ribosomal RNA (rRNA) [15]. While multiple theoretical and experimental studies addressed charge transport in DNA [16][17][18][19], such studies for RNA [14,20,21] are rare. Very recently, it was shown that charge transport along the DNA molecule plays important role in regulation of the replication process [18] and DNA repair [19], and disruption of DNA conductivity may cause severe diseases [22].…”