Double-strand damage

Since DNA is double-strand, damage to one strand of the DNA can often be repaired by using the undamaged complementary strand as a template to direct new incorportion of correct deoxynucleotides in place of the removed incorrect ones. 

Ionising radiation can cause double-strand damage. If this happens, then the repair process may not be completely accurate, resulting in a mutation in the DNA and possibly cellular malfunction, e.g. skin cancer. 

The biological activity of calicheamicin 4 (simplified structure) is based on the ability to damage DNA. At the reaction site, initially the distance between the triple bonds is diminished by an addition reaction of a sulfur nucleophile to the enone carbon-carbon double bond, whereupon the Bergman cyclization takes place leading to the benzenoid diradical 5, which is capable of cleaving double-stranded DNA." ... 

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]. 

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... 

In addition to causing DNA strand breaks, tirapazamine damages the heterocyclic base residues of double-stranded DNA.2 " 2 Similar to authentic, radiolytically generated hydroxyl radical, the drug causes approximately four times more base... 

Oxaliplatin (Eloxatin ) is similar to other platinum analogs (e.g., cisplatin) in that it binds to the N-7 position of guanine, which results in cross-linking of DNA and double-stranded DNA breaks.26,40 Oxaliplatin differs from cisplatin in that the DNA damage induced by oxaliplatin may not be as easily recognized by DNA repair genes often seen in colorectal cancer. Oxaliplatin, in combination with 5-FU-based regimens, is indicated for the first- and second-line treatment of metastatic colon cancer, as well as the adjuvant treatment of colon cancer. 

The cycloreversion experiments showed a clean Tf=T-DNA to T/T-DNA transformation. No by-products were detected, which supports the idea that DNA may be more stable towards reduction compared to oxidation. Even heating the irradiated DNA with piperidine furnished no other DNA strands other then the repaired strands, showing that base labile sites - indicative for DNA damage - are not formed in the reductive regime. The quantum yield of the intra-DNA repair reaction was therefore calculated based on the assumption that the irradiation of the flavin-Tf=T-DNA strands induces a clean intramolecular excess electron transfer driven cycloreversion. The quantum yield was found to be around 0=0.005, which is high for a photoreaction in DNA. A first insight into how DNA is able to mediate the excess electron transfer was gained with the double strands 11 and 12 in which an additional A T base pair compared to 7 and 8 separates the dimer and the flavin unit. 

Figure 2 Double-stranded oligonucleotide photoprobes that simulate modified DNA and intended to cross-link to DNA-binding proteins. (A) Probe modeling interstrand cross-linking by cisplatin Source From Ref. [63], with permission from the American Chemical Society via the Rightslink service (license number 2458870278307 granted June 30, 2010). The benzophenone probe prior to reaction with DNA is shown in the lower part of the panel. (B) Photoaffinity probe for bacterial DNA repair proteins. TT is a simulated thymine dimer intended to be recognized as a site of damage in DNA, and T (two instances) is the diazirine thymine derivative T Source From Ref. [64], with permission from Wiley.

Many quinones (including anthracyclines considered above) are well-known prooxidants that makes them potential DNA damaging agents. It has been shown that menadione (2-methyl-1,4-naphthoquinone), a redox cycling quinone, induced single- and double-strand... 

Ueda K, Kinoshita Y, Xu ZJ, Ide N, Ono M, Akahori Y, Tanaka I, Inoue M (2000) Unusual core histones specifically expressed in male gametic cells of Lilium longiflorum. Chromosoma 108 491—500 Unal E, Arbel-Eden A, Sattler U, Shroff R, Lichten M, Haber JE, Koshland D (2004) DNA damage response pathway uses histone modification to assemble a double-strand break-specific cohesin domain. Mol Cell 16 991-1002... 

In Saccharomyces cerevisiae, multiple histone H2A phosphorylation sites have been characterized (Serine 122, Serine 129, Threonine 126) (Wyatt et al, 2003 Harvey et al, 2005 Redon et al, 2006). Histone H2A (S129) is essential for DNA double-strand-break responses (see Section 4) and histone H2A (SI22) is important for survival in the presence of DNA damage (Harvey et al, 2005) (Fig. 2). 

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