Strand breaks in DNA

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. 

Topotecan inhibits topoisomerase I to cause single-strand breaks in DNA. The pharmacokinetics of topotecan can be described by a two-compartment model, with a terminal half-life of 80 to 180 minutes, with renal clearance accounting for approximately 70% of the clearance.19 Topotecan has shown clinical activity in the treatment of ovarian and lung cancer, myelodysplastic syndromes, and acute myelogenous leukemia. The intravenous infusion may be daily for 5 days or once weekly. Side effects include myelosuppression, mucositis, and diarrhea. 

Van Dyck, E., et al.. Binding of double-strand breaks in DNA by human Rad52 protein. Nature, 1999, 398(6729), 728-31. 

It is well-known that many organic excited states (e.g. the triplet state of benzophenone) can effectively abstract hydrogen atoms from organic compounds such as alkanes and alcohols. This behaviour is not commonly found for metal-containing compounds - a notable exception being the lowest excited state of uranyl ion which abstracts H atoms from alcohols, sugars etc., with the resultant formation of free radicals and U(V) compounds. Recent work has shown that it is very effective in inducing strand breaks in DNA (see Sect. 8). 

Antibiotics Two antibiotics have been used in cancer therapy actomyosin D which binds to DNA and prevents proliferation, and bleomycins which cause single-strand breaks in DNA. 

Enflurane caused single-strand breaks in DNA in human lymphocytes tested in vitro. Damage was dose dependent, but large individual variations in DNA repair were noted. 

Doxorubicin binds tightly to DNA by its ability to intercalate between base pairs and therefore is preferentially concentrated in nuclear structures. Intercalation results in steric hindrance, hence production of single-strand breaks in DNA and inhibition of DNA synthesis and DNA-dependent RNA synthesis. The enzyme topoisomerase II is thought to be involved in the generation of DNA strand breaks by the anthracydines. Cells in S-phase are most sensitive to doxorubicin, although cytotoxicity also occurs in other phases of the cell cycle. 

Von Sonntag [7] has estimated that the direct effects contribute about 40% to cellular DNA damage, while the effects of water radicals amount to about 60%. A paper by Krisch et al. [15] on the production of strand breaks in DNA initiated by HO radical attack has the direct effects contribution at 50%. 

Takakura, K. Ishikawa, M. Ito, T. Action spectrum for the induction of single-strand breaks in DNA in buffered aqueous solution in the wavelength range from 150 to 272 nm dual mechanism. Int. J. Radiat. Biol. 1987, 52 (5), 667-675. 

Takakura, K. Maezawa, H. Kobayashi, K. Hieda, K. Strand breaks in DNA in buffered solution induced by monochromatic X-rays around the K-shell absorption edge of phosphorus. In Synchrotron Radiation in Biosciences. Chance, B., Deisenhofer, J., Ebashi, S., Goodhead, D.T., Helliwell, J.R., Huxley, H.E., lizuka, T., Kirz, J., Mitsui, T., Rubenstein, E., Sakabe, N., Schmahl, G., Stuhrmann, H.B., Wuthrich, K., Zaccai, G., Eds. Oxford University Press Oxford, 1994 756-764 pp. 

Takakura, K. Double-strand breaks in DNA induced by the K-shell ionization of calcium atoms. Acta Oncol. 1996, 35 (7), 883-888. 

Finally, the peroxynitrite formed from the RNS and ROS can cause single-strand breaks in DNA, and this activates PARP, which transfers ADP-ribose from NAD+ to nuclear proteins. This consumes NAD+, which means that NADH levels are compromised, and hence ATP is again affected. The resynthesis of NAD+ also consumes more ATP. 

Compounds such as hydrogen peroxide and alkylating agents such as dimethyl sulfate, which cause single-strand breaks in DNA, cause the activation of the enzyme PARP. This... 

Solveig Walles, S.A. Erixon, K. (1984) Single-strand breaks in DNA of various organs of mice induced by methyl methanesulfonate and dimethysulfoxide determined by the alkaline unwinding technique. Carcinogenesis, 5, 319-323... 

One circumstance that triggers this control mechanism is the presence of single-strand breaks in DNA, which leads to arrest of the cell cycle in G2. A specific protein ldnase (called Rad3 in yeast), which is activated by single-strand breaks, triggers a cascade leading to the inactivation of the phosphatase that dephosphorylates Tyr15 of CDK. The CDK remains inactive and the cell is arrested in G2. The cell will not divide until the DNA is repaired and the effects of the cascade are reversed. 

Somatic hypermutation, 41-51 Southern blots, 7,22, 33 Strand breaks in DNA, 129, 132... 

Chatterjee A, Magee JL (1985) Theoretical investigation of the production of strand breaks in DNA by water radicals. Radiat Protect Dosimetry 13 137-140 Deeble DJ, von Sonntag C (1984) y-Radiolysis of poly(U) in aqueous solution. The role of primary sugar and base radicals in the release of undamaged uracil. Int J Radiat Biol 46 247-260 Deeble DJ, von Sonntag C (1986) Radiolysis of poly(U) in oxygenated solutions. Int J Radiat Biol 49 927-936... 

A simpler, quicker, and less expensive cytogenetic test uses sister chromatid exchange (SCE). SCEs are detected in chromosomes that have been treated in such a way that the two sister chromatids of a chromosome differ chemically and thus stain differently. Most chemical mutagens induce SCEs at concentrations lower by a factor of about 100 than those needed to produce significant yields of ordinary chromosomal aberrations. The major exception to this is the small group of chemicals that, like x rays, produce double strand breaks in DNA and induce aberrations at all stages of the cell cycle. 

---