Strand break

Most studies of DNA damage centre on strand breaks, partly because they are relatively easy to study. Also, there is a large (but controversial) body of opinion that implicates double strand breaks (DSB) as the major lesion leading to cell death. It seems that single strand breakage (SSB) and base damage that does not lead to strand breakage are less important. 

There are a variety of techniques available for studying strand breakage. These are in general use in all studies of DNA and are in no sense special for radical studies. We therefore confine ourselves to a brief summary of the methods. 

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Rejection criteria for the ropes resulting in durability loss, are defined by the regulations character and number of wires broken strand breakes friction wear corrosion ... 

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). 

Administration of dipyridamole-AMP to mice 5—25 min after 1 Gy (100 rad) of TBI y-kradiation is also protective, as indicated by plasma thymidine levels and the amount of saline soluble polynucleotides in the thymus (112). Adding dipyridamole-AMP to in vitro kradiated suspensions of thymocytes enhances the rejoining of DNA strand breaks (112). These post-kradiation effects ate presumably mediated by the activation of extraceUulat adenosine receptors. 

The key to hexavalent chromium s mutagenicity and possible carcinogenicity is the abiHty of this oxidation state to penetrate the cell membrane. The Cr(VI) Species promotes DNA strand breaks and initiates DNA—DNA and DNA-protein cross-links both in cell cultures and in vivo (105,112,128—130). The mechanism of this genotoxic interaction may be the intercellular reduction of Cr(VI) in close proximity to the nuclear membrane. When in vitro reductions of hexavalent chromium are performed by glutathione, the formation of Cr(V) and glutathione thiyl radicals are observed, and these are beHeved to be responsible for the formation of the DNA cross-links (112). 

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.

Chromosomal aberrations Gene mutation Dominant lethal mutation Micronucleus formation Micronucleus formation Micronucleus formation Chromosomal aberrations Sister chromatid exchange Micronucleus formation Chromosomal aberrations Sister chromatid exchange DNA-protein cross-links Nondisjunction of Y chromosome in sperm DNA damage (single-strand breaks)... 

Nelson MA, Bull RJ. 1988. Induction of strand breaks in DNA by trichloroethylene and metabolites in rat and mouse liver in vivo. Toxicol Appl Pharmacol 94 45-54. 

Walles SAS. 1986. Induction of single-strand breaks in DNA of mice by trichloroethylene and tetrachloroethylene. Toxicol Lett 31 31-35. 

ASTLEY s B, ELLIOTT R M, ARCHER D B and souTHON s (2002) Increased cellular carotenoid levels reduce the persistance of DNA single strand breaks following oxidative chaUange. Nutrition and Cancer. In press. 

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