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

Abstract

During cancer radiation therapy high-energy radiation is used to reduce tumour tissue. The irradiation produces a shower of secondary low-energy (<20 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 (8.8 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'-(TTA GGG) is more sensitive to low-energy electrons than an intermixed sequence 5'-(TGT GTG A) confirming the unique electronic properties resulting from G-stacking. With increasing length of the oligonucleotide (i.e., going from 5'-(GGG ATT) to 5'-(GGG ATT) ), 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.

Vacuum‐UV and Low‐Energy Electron‐Induced DNA Strand Breaks – Influence of the DNA Sequence and Substrate

“…The comparison of the obtained cross sections for SSBs is visualized in Figure C. The lowest cross section for SSBs was obtained for 5′‐d(G 12 ) with a value of (3.1±0.2) ⋅ 10 −15 cm 2 while the other cross sections for SSBs of 5′‐d(X 12 ) X=A, C, T are very similar and vary from (3.4±0.5) to (3.9±0.4) ⋅ 10 −15 cm 2 . In Table it can be seen that these results are in a very good agreement and in the same dimension like experiments done so far with oligonucleotides in this energy range ,. Boudaïffa et al .…”

“…Comparing G rich sequences (Table ) it is demonstrated that 5′‐d(TT(GGG ATT) 2 T) with σ(5′‐d(TT(GGG ATT) 2 T))=(6.8±0.5) ⋅ 10 −15 cm 2[11] has a higher cross section for SSBs than 5′‐d(G 12 ) followed by 5′‐d(TGT GTG A) 2 T). An A base located next to a G‐stack leads to a polarization with a partial positive charge on the G stack, which can result in an increased cross section for LEE induced SSBs, which is even higher than the cross section found for d(G 12 ). This is reasonable considering that the 5′‐d(G 12 ) sequence is most likely not polarized.…”

“…The energy used here for LEE irradiation (8.8 eV) corresponds to the maximum yield of SSBs observed previously with plasmid DNA . Additionally, it is close enough to the photon energy used here to allow for comparison of the strand break characteristics upon VUV photon and LEE irradiation determined also in previous experiments . LEEs can induce DNA strand breaks by DEA (see below and SI.4 for detailed explanations), which is a resonant process ,.…”

“… [a] Rackwitz et al ., [b] Schürmann et al ., [c] Keller et al ., [d] Li et al ., [e] Park et al . *The cross section values reported in were determined using an electron current measured directly on the sample.…”

“…Especially at very low energies (<10 eV) LEEs are known to induce DNA damage very effectively by dissociative electron attachment (DEA) ,. Different groups reported high strand break yields in the electron energy region below 10 eV using either short oligonucleotides, or plasmid DNA . Even LEEs of an energy below 1 eV are very effective in inducing strand breakage ,…”