Double-strand break

The outcome of rapid radiation chemical processes in mammalian cells is to cause a variety of longer-Hved physical alterations in the DNA. Of these, double-strand breaks (DSBs) appear to be most frequently involved in cell killing if not correctly repaired. In general, thiols protect against DSB induction in proportion to their effect on cell killing (7), although there are exceptions (8). 

When coRI encounters this sequence in dsDNA, it causes a staggered, double-stranded break by hydrolyzing each chain between the G and A residues ... 

Epipodophyllotoxins (etoposide, teniposide) are derived from mandrake root (Podophyllum peltatum). They inhibit topoisomerase H thus causing double strand breaks. Cells in S- and G2-phases are most sensitive. Unwanted effects include nausea and vomiting, myelosuppression, and hair loss. 

Camptothecins (irinotecan, topotecan) are derived from the bark of the Chinese tree Xi Shu (Camptotheca accuminata). They inhibit topoisomerase I thus effecting double strand breaks. Unwanted effects include diarrhea and reversible bone marrow depression. 

Thus, the AR directly protect DNA from the UV-damage. This is manifested in the saving of the total amount of this biopolymer, preventing its deep degradation due to formation of double-stranded breaks, as well as preventing the single -stranded breaks without transition of supercoiled into the relaxed circular form of DNA. Evidence of effects increased with length of the alkyl radical of the AR molecule and with AR concentration increase. 

In turn, an important factor that can damage DNA in nature or at performing molecular genetic studies, is ultraviolet (UV) radiation that is absorbed by this biopolymer at bandwidth maxmum 254 nm. This led to the formation of different DNA photodamages, with increasing of the dose of UV radiation progressed from pyrimidine dimers to single-and double-stranded breaks [Cariello et al., 1988 Lyamichev et al., 1990]. 

The repair of double-strand breaks is part of the physiologic process of immunoglobulin gene rearrangement. It... 

Figure 36-25. Double-strand break repair of DNA. The proteins Ku and DNA-dependent protein kinase combine to approximate the two strands and unwind them. The aligned fragments form base pairs the extra ends are removed, probably by a DNA-PK-associated endo- or exonuclease, and the gaps are filled in and continuity is restored by ligation.

Subjecting cells to oxidative stress can result in severe metabolic dysfunctions, including peroxidation of membrane lipids, depletion of nicotinamide nucleotides, rises in intracellular free Ca ions, cytoskeletal disruption and DNA damage. The latter is often measured as formation of single-strand breaks, double-strand breaks or chromosomal aberrations. Indeed, DNA damage has been almost invariably observed in a wide range of mammalian cell types exposed to oxidative stress in a number... 

Topoisomerase is responsible for relieving the pressure on the DNA structure during unwinding by producing strand breaks. Topoisomerase I produces single-strand breaks, whereas topoisomerase II produces double-strand breaks. 

Etoposide causes multiple DNA double-strand breaks by inhibiting topoisomerase II. The pharmacokinetics of etoposide are described by a two-compartment model, with an a half-life of 0.5 to 1 hour and a (5 half-life of 3.4 to 8.3 hours. Approximately 30% of the dose is excreted unchanged by the kidney.16 Etoposide has shown activity in the treatment of several types of lymphoma, testicular and lung cancer, retinoblastoma, and carcinoma of unknown primary. The intravenous preparation has limited stability, so final concentrations should be 0.4 mg/mL. Intravenous administration needs to be slow to prevent hypotension. Oral bioavailability is approximately 50%, so oral dosages are approximate two times those of intravenous doses however, relatively low oral daily dosages are used for 1 to 2 weeks. Side effects include mucositis, myelosuppression, alopecia, phlebitis, hypersensitivity reactions, and secondary leukemias. 

Frankenberg-Schwager, M., D. Frankenberg, D. Blocher, and C. Adamczyk, The Linear Ralationship Between DNA Double-Strand Breaks and Radiation Dose (30 MeV Electrons) is Converted Into a Quadratic Function by Cellular Repair, Internat. J. Radiation Biology 37 207-212 (1980). 

Hopfner, K. P., Karcher, A., Shin, D. S., Craig, L., Arthur, L. M., Carney, J. P. and Tainer, J. A. (2000). Structural biology of Rad50 ATPase ATP-driven conformational control in DNA double-strand break repair and the ABC-ATPase superfamily, Cell, 101, 789-800. 

Bradley, M.O., Dysart, G., Fitzsimmons, K., Harback, P., Lewin, J. and Wolf, G. (1982). Measurement hy filter elution of DNA single- and double-strand breaks in rat hepatocytes Effects of nitrosamines and y-irradiation. Cancer Res. 42 2569-2597. 

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