Sensitizing DNA Towards Low‐Energy Electrons with 2‐Fluoroadenine

Abstract

2-Fluoroadenine ( 2F A) is atherapeutic agent, which is suggested for application in cancer radiotherapy. The molecular mechanism of DNAr adiation damage can be ascribed to as ignificant extent to the action of low-energy (< 20 eV) electrons (LEEs), which damage DNAbydissociative electron attachment. LEE induced reactions in 2F Aa re characterized both isolated in the gas phase and in the condensed phase when it is incorporated into DNA. Information about negative ion resonances and anion-mediated fragmentation reactions is combined with an absolute quantification of DNAstrand breaks in 2F A-containing oligonucleotides upon irradiation with LEEs.T he incorporation of 2F A into DNAresults in an enhanced strand breakage.The strandbreak cross sections are clearly energy dependent, whereas the strand-break enhancements by 2F Aa t5 .5, 10, and 15 eV are very similar.T hus, 2F Ac an be considered an effective radiosensitizer operative at awide range of electron energies.Radiation therapy using high-energy photons,e lectrons,o r ions belongs to the most important methods used to treat cancer. As was shown in recent years,t he radiation damage induced by the high-energy primary radiation is mostly due to the effect of low-energy secondary particles generated along the ionization track. [1,2] Low-energy electrons (LEEs) belong to the most important intermediates,since they are produced in significant quantities [2,3] and can directly attach to DNA and other biomolecules to form transient negative ions,which are unstable towards dissociation. [4] In DNA, dissociative electron attachment (DEA) can result in effective single and double strand breaks. [5,6]

Low‐Energy Electron‐Induced Strand Breaks in Telomere‐Derived DNA Sequences—Influence of DNA Sequence and Topology

“…DNA single-strand breaks can be induced by LEEs via DEA within several resonances below 12 eV (depending on the system under study resonances peaking around1 0, 7, 5.5, 2.2 and 1eVh ave been reported). [6][7][8][9][10][11][12] In av ery recent study the energy-dependenceo fLEE-induced strand breakage in two different oligonucleotides has been determined. [12] Ab road resonance peakinga round 7eVw as found whereas resonances at lower energies are of minor importance for the strand breakage.…”

“…An alternative pathway for dissociation after electron attachment is autoionization of the extra electron accompanied by excitation into a dissociative state (neutral dissociation). DNA single‐strand breaks can be induced by LEEs via DEA within several resonances below 12 eV (depending on the system under study resonances peaking around 10, 7, 5.5, 2.2 and 1 eV have been reported) . In a very recent study the energy‐dependence of LEE‐induced strand breakage in two different oligonucleotides has been determined .…”

The Physico‐Chemical Basis of DNA Radiosensitization: Implications for Cancer Radiation Therapy

“…[49] By using the DNA origami technique it was demonstrated that incorporation of 2F Ai nto oligonucleotides leads to an enhancemento fe lectron-induced strand breaks by af actor of 1.6-1.7 at the electron energies of 5.5, 10.0 and 15.0 eV (see Figure 5). [35] At the same time the strand break cross-sections are clearly energy-dependent with the highest cross-section found at 5.5 eV,w hich confirms that strand breakage occurs by resonant DEA. Indeed, gas-phase DEA measurements of 2F Ah ave shown ac lear DEA resonance at around 5.5 eV,w hich results in the abstractiono fHand F from 2F A[ Eq.…”

“…The strand breaks are quantified in terms of absolutec ross-sections for SSBs. [18] This technique allows to study the sequence dependenceo f low-energy radiation-induced strand breaks, [18,19] the effect of radiosensitizers, [18,34,35] and highero rder DNA structures. [34] The error in the measurements is typicallyq uite small (in the range of 1-15 %), [36] and recently,w ec ould show that ag reater structural variation of the target sequences resultsi nal arger experimentale rror.…”

DNA nanostructures: A versatile lab-bench for interrogating biological reactions

“…Following selective radiation exposure, the absolute cross-section of DNA strand breakages was directly quantified by the resultant streptavidin patterns atop the DNA origami. This elegant approach was used to assess the radiation susceptibility of G-quadruplex-rich telomeric DNA regions [82], the impact on specific DNA sequences [83] and the effects of several clinically relevant radiotherapy photosensitisers [84] [85]. This concept can be expanded through the introduction of DNA aptamers to remove the limitation of detection via hybridisation or damage of nucleic acids.…”