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[en] The influence of radioprotectors (P) (cysteine, cysteamine) and hematoporphyrin on the yields of malonic dialdehyde and an unidentified carbonyl compound from the radiolysis of 2-deoxy-D-ribose (DR) in aqueous N2O- or air-saturated solutions was studied. The experimental yields (G) were compared with the calculated (Gc) ones on the basis of the study of competition between P and DR for the H atoms and OH radicals. The values of G/Gc < 1 can be explained by the repair of DR via H transfer from P to DR
[en] Epigenetic mechanisms assist in maintaining gene expression patterns and cellular properties in developing and adult tissues. The molecular pathology of disease states frequently includes perturbation of DNA and histone methylation patterns, which can activate apoptotic pathways associated with maintenance of genome integrity. This perspective focuses on the pathways linking DNA methyltransferases and methyl-CpG binding proteins to apoptosis, and includes new bioinformatic analyses to characterize the evolutionary origin of two G/T mismatch-specific thymine DNA glycosylases, MBD4 and TDG
[en] The E3 ubiquitin ligases ring finger protein (RNF) 8 and RNF168 transduce the DNA double-strand break (DSB) response (DDR) signal by ubiquitinating DSB sites. The depletion of RNF8 or RNF168 suppresses the accumulation of DNA-repair regulating factors such as 53BP1 and RAP80 at DSB sites, suggesting roles for RNF8- and RNF168-mediated ubiquitination in DSB repair. This mini-review provides a brief overview of the RNF8- and RNF168-dependent DDR-signaling and DNA-repair pathways. The choice of DNA-repair pathway when RNF8- and RNF168-mediated ubiquitination-dependent DDR signaling is negatively regulated by deubiquitinating enzymes (DUBs) is reviewed to clarify how the opposing roles of RNF8/RNF168 and DUBs regulate ubiquitination-dependent DDR signaling and the choice of DNA-repair pathway
[en] The purpose of this study was to examine the repair of radiation-induced potentially lethal damage in A431 and CaSki cells after chronic hypoxia. Cells in exponential phase are subjected to hypoxia (<10 ppm oxygen) for up to 12 h and then are allowed to reoxygenate in air for up to 4 h. Cells are then irradiated with γ rays. Cell survivals are measured by clonogenic assay immediately and at different times after irradiation. Compared to aerobic controls, an increase in the level of potentially lethal damage repair (PLDR) is demonstrated in A431 cells reoxygenated for 10 min after >4 h of hypoxia. The repair returned to aerobic control level by 3 h of reoxygenation. PLDR of A431 cells reached maximum at about 9 h after irradiation in cells reoxygenated for 10 min after hypoxia. However, the repair is maximum at 6 h in cells reoxygenated for 3 h after hypoxia and in aerobic cells not previously exposed to hypoxia. Reoxygenation after chronic hypoxia did not affect the PLDR capacity and repair kinetics of CaSki cells. The results suggest that radiosensitization by reoxygenation after chronic hypoxia is not related to inhibition of PLDR. 14 refs., 3 figs
[en] DNA repair is crucial to the survival of all organisms. The bacterial RecA protein is a central component in the SOS response and in recombinational and SOS DNA repairs. The RecX protein has been characterized as a negative modulator of RecA activity in many bacteria. The recA and recX genes of Herbaspirillum seropedicae constitute a single operon, and evidence suggests that RecX participates in SOS repair. In the present study, we show that the H. seropedicae RecX protein (RecX_H_s) can interact with the H. seropedicae RecA protein (RecA_H_s) and that RecA_H_s possesses ATP binding, ATP hydrolyzing and DNA strand exchange activities. RecX_H_s inhibited 90% of the RecA_H_s DNA strand exchange activity even when present in a 50-fold lower molar concentration than RecA_H_s. RecA_H_s ATP binding was not affected by the addition of RecX, but the ATPase activity was reduced. When RecX_H_s was present before the formation of RecA filaments (RecA-ssDNA), inhibition of ATPase activity was substantially reduced and excess ssDNA also partially suppressed this inhibition. The results suggest that the RecX_H_s protein negatively modulates the RecA_H_s activities by protein-protein interactions and also by DNA-protein interactions
[en] Background and purposeHPV-positive HNSCC cells are characterized by radiosensitivity, inefficient DNA double-strand break repair and a profound and prolonged arrest in G2. Here we explored the effect of clinically relevant inhibitors of Chk1 and Wee1 to inhibit the radiation-induced G2-arrest in order to achieve further radiosensitization.
[en] Hyperthermia (HT) acts as a cancer treatment by direct cell killing, radiosensitization, and promotion of tumor reoxygenation. The sensor proteins of the DNA damage response (DDR) are the direct targets of HT. However, the spatiotemporal properties of sensor proteins under HT are still unclear. Therefore, investigating the impact of HT on sensor proteins is of great importance. In the present study, the human fibrosarcoma cell line HT1080 stably transfected with 53BP1-GFP [the DDR protein 53BP1 fused to green fluorescent protein (GFP)] was used to investigate the real-time cellular response to DNA double-strand breaks (DSBs) induced by γ-rays. Using live-cell imaging combined with HT treatment, the spatiotemporal properties of the 53BP1 protein were directly monitored and quantitatively studied. We found that HT could delay and decrease the formation of 53BP1 ionizing radiation–induced foci (IRIF). Moreover, through the in situ tracking of individual IRIF, it was found that HT resulted in more unrepaired IRIF over the period of observation compared with IR alone. Additionally, the unrepaired IRIF had a larger area, higher intensity, and slower repair rate. Indeed, almost every cell treated with HT had unrepaired IRIF, and the majority of these IRIF increased in area individually, while the rest increased in area by the merging of adjacent IRIF. In summary, our study demonstrated that HT could perturb the primary event in the DDR induced by IR, and this may have important implications for cancer treatment and heat radiosensitization.
[en] The purpose of this study was to examine whether 3-amino-benzamide (3ABA), an inhibitor of poly (ADP-ribose) synthesis, inhibits the two types of potentially lethal damage (PLD) repair, termed slow and fast. The fast-type PLD repair was measured by the decrease in survival of V79 Chinese hamster cells by postirradiation treatment with 3ABA. The slow-type PLD repair was measured by the increase in survival by posttreatment with conditioned medium (CM), which became conditioned by growing a crowed culture of cells and supports the slow-type PLD repair. Up to 1 mM 3-ABA inhibited the slow type repair; at doses of 2 mM and above, it inhibited the fast type of PLD repair. There are quantitative differences in cellular effects of 3ABA dependent on concentration. Poly (ADP-ribose) appears to play an important role in the PLD repairs and has little effect on the repair of sublethal damage. 10 refs., 2 figs
[en] Ataxia-telangiectasia (A-T) is the classic human genetic disease involving severe ionizing radiation sensitivity and as such has been intensely studied by radiation biologists over the years. Unlike its counterpart for UV light sensitivity -xeroderma pigmentosum - A-T has no obvious DNA repair defect; and there has been much speculation as to the mechanism underlying the altered radioresponses associated with this disease. The gene defective in A-T (ATM) has recently been cloned, and its primary coding sequence determined. The primary sequence of the ATM protein suggests that it has some regulatory functions related to cellular radioresponse and maintenance of genomic stability, and shares these functions with a growing family of other proteins in various organisms. At this juncture it is appropriate to review our current knowledge about the radiobiology of A-T and reflect on the possible radiobiological mechanisms that are suggested by the ATM gene itself. This article will attempt briefly to review current knowledge about the radiobiology of A-T and to introduce new speculations about underlying radiobiological mechanisms that are suggested by the primary amino acid sequence of the predicted ATM gene product. (Author)
[en] The accuracy of DNA repair may play a role in determining the cytotoxic effect of ionizing radiation. Repair, as measured by DNA strand breakage, often shows little difference between tumor cell lines of widely different radiosensitivity. The mechanism by which DNA fragments are rejoined is poorly understood. This study used plasmid transfection as a probe to assess the balance between correct repair and misrepair. A general trend for sensitive cells to show lower repair fidelity relative to resistant cells was observed. The type of double-strand cleavage of the plasmid (staggered or blunt) made little difference to the measured repair fidelity, in contrast to published studies in which restriction-enzyme breaks had been introduced into DNA within chromatin. Specific comparison of parent lines and their radiosensitive clones showed significant differences in repair fidelity for a relatively small change in radiation response, which was in line with the overall correlation. These same pairs have previously been shown to have no difference in the loss of DNA fragmentation with time after irradiation, and Southern analysis had confirmed the integrated plasmid copy number was similar in the cell lines compared. The number of intact copies of the damaged gene relative to the undamaged gene mirrored the observed repair fidelity. However, in one cell line out of the 10 studied, an exception to the observed trend was found. In comparison of two equally radioresistant bladder cancer cell lines, large differences in repair fidelity were observed. Again, no difference in the integrated copy number was found, and the damaged gene was highly rearranged or deleted in the cell line with low repair fidelity. It is suggested that repair fidelity can be, but is not invariably, a measure of correct repair relative to misrepair, resulting from the processing of double-strand breaks and, hence, the response to ionizing radiation. 24 refs., 2 figs., 2 tabs