RESUMO
During cancer radiation therapy high-energy radiation is used to reduce tumour tissue. The irradiation produces a shower of secondary low-energy (<20â eV) electrons, which are able to damage DNA very efficiently by dissociative electron attachment. Recently, it was suggested that low-energy electron-induced DNA strand breaks strongly depend on the specific DNA sequence with a high sensitivity of G-rich sequences. Here, we use DNA origami platforms to expose G-rich telomere sequences to low-energy (8.8â eV) electrons to determine absolute cross sections for strand breakage and to study the influence of sequence modifications and topology of telomeric DNA on the strand breakage. We find that the telomeric DNA 5'-(TTAâ GGG)2 is more sensitive to low-energy electrons than an intermixed sequence 5'-(TGTâ GTGâ A)2 confirming the unique electronic properties resulting from G-stacking. With increasing length of the oligonucleotide (i.e., going from 5'-(GGGâ ATT)2 to 5'-(GGGâ ATT)4 ), both the variety of topology and the electron-induced strand break cross sections increase. Addition of K+ ions decreases the strand break cross section for all sequences that are able to fold G-quadruplexes or G-intermediates, whereas the strand break cross section for the intermixed sequence remains unchanged. These results indicate that telomeric DNA is rather sensitive towards low-energy electron-induced strand breakage suggesting significant telomere shortening that can also occur during cancer radiation therapy.
Assuntos
DNA/efeitos da radiação , Telômero/metabolismo , Dano ao DNA , Elétrons , Quadruplex G , Neoplasias/radioterapia , FototerapiaRESUMO
2-Fluoroadenine ((2F) A) is a therapeutic agent, which is suggested for application in cancer radiotherapy. The molecular mechanism of DNA radiation damage can be ascribed to a significant extent to the action of low-energy (<20â eV) electrons (LEEs), which damage DNA by dissociative electron attachment. LEE induced reactions in (2F) A are 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 DNA strand breaks in (2F) A-containing oligonucleotides upon irradiation with LEEs. The incorporation of (2F) A into DNA results in an enhanced strand breakage. The strand-break cross sections are clearly energy dependent, whereas the strand-break enhancements by (2F) A at 5.5, 10, and 15â eV are very similar. Thus, (2F) A can be considered an effective radiosensitizer operative at a wide range of electron energies.
Assuntos
Adenina/análogos & derivados , DNA/química , Elétrons , Teoria Quântica , Adenina/químicaRESUMO
The combination of the Ugi four-component reaction (Ugi-4CR) with acyclic diene metathesis (ADMET) or thiol-ene polymerization led to the formation of poly-1-(alkylcarbamoyl) carboxamides, a new class of substituted polyamides with amide moieties in the polymer backbone, as well as its side chains. 10-Undecenoic acid, obtained by pyrolysis of ricinoleic acid, the main fatty acid of castor oil, was used as the key renewable building block. The use of different primary amines, as well as isonitriles (isocyanides) for the described Ugi reactions provided monomers with high structural diversity. Furthermore, the possibility of versatile post-modification of functional groups in the side chains of the corresponding polymers should be of considerable interest in materials science. The obtained monomers were polymerized by ADMET, as well as thiol-ene, chemistry and all polymers were fully characterized. Finally, ortho-nitrobenzylamide-containing polyamides obtained by this route were shown to be photoresponsive and exhibited a dramatic change of their properties upon irradiation with light.
RESUMO
We have characterized ultraviolet (UV) photon-induced DNA strand break processes by determination of absolute cross sections for photoabsorption and for sequence-specific DNA single strand breakage induced by photons in an energy range from 6.50 to 8.94 eV. These represent the lowest-energy photons able to induce DNA strand breaks. Oligonucleotide targets are immobilized on a UV transparent substrate in controlled quantities through attachment to DNA origami templates. Photon-induced dissociation of single DNA strands is visualized and quantified using atomic force microscopy. The obtained quantum yields for strand breakage vary between 0.06 and 0.5, indicating highly efficient DNA strand breakage by UV photons, which is clearly dependent on the photon energy. Above the ionization threshold strand breakage becomes clearly the dominant form of DNA radiation damage, which is then also dependent on the nucleotide sequence.
Assuntos
Dano ao DNA/efeitos da radiação , DNA de Cadeia Simples/química , DNA/química , Nanoestruturas/química , Fótons , Raios Ultravioleta , Microscopia de Força AtômicaRESUMO
The electronic structure of DNA is determined by its nucleotide sequence, which is for instance exploited in molecular electronics. Here we demonstrate that also the DNA strand breakage induced by low-energy electrons (18â eV) depends on the nucleotide sequence. To determine the absolute cross sections for electron induced single strand breaks in specific 13â mer oligonucleotides we used atomic force microscopy analysis of DNA origami based DNA nanoarrays. We investigated the DNA sequences 5'-TT(XYX)3TT with X = A, G, C and Y = T, BrU 5-bromouracil and found absolute strand break cross sections between 2.66 · 10(-14)â cm(2) and 7.06 · 10(-14)â cm(2). The highest cross section was found for 5'-TT(ATA)3TT and 5'-TT(ABrUA)3TT, respectively. BrU is a radiosensitizer, which was discussed to be used in cancer radiation therapy. The replacement of T by BrU into the investigated DNA sequences leads to a slight increase of the absolute strand break cross sections resulting in sequence-dependent enhancement factors between 1.14 and 1.66. Nevertheless, the variation of strand break cross sections due to the specific nucleotide sequence is considerably higher. Thus, the present results suggest the development of targeted radiosensitizers for cancer radiation therapy.