DNA oxidation 4788141 193747921 2008-02-24T19:06:14Z Canaantt 6502047 {{context}} '''DNA oxidation''' is the process of oxidative damage on [[Deoxyribonucleic Acid]]. It occurs most readily at [[guanine]] residues due to the low [[oxidation]] potential of this base relative to [[cytosine]], [[thymine]], and [[adenine]]. It is widely believed to be linked to certain disease and cancers. {{Unreferenced|date=May 2007}} [[Category:Organic redox reactions]] {{biology-stub}}'''RNA Oxidation''' [[RNAs]] in native milieu are exposed to various insults. Among those threats, [[oxidative stress]] is one of major reasons that cause damage to RNAs. Level of oxidative stress that cell is enduring is reflected by the quantity of Reactive oxidative species (ROS). ROS are generated from normal oxygen metabolism in cells, recognized as a list of active molecules, such as free radicals O<sup>2-</sup>, <sub>1</sub>O<sup>2</sup>, H<sub>2</sub>O<sub>2</sub> and, •OH .<ref>Buechter, DD. (1988) [[Free radicals]] and oxygen toxicity.Pharm Res. 5:253-60.</ref> [[Nucleic acid]] can be oxidized by ROS through [[Fenton reaction]] <ref>Wardman, P. and Candeias, L.P. (1996). Fenton chemistry: an introduction. Radiat. Res. 145, 523–531.</ref>.To date, around 20 oxidative lesions have been discovered in DNA.<ref>Cooke, M. S., Evans, M. D., Dizdaroglu, M., Lunec, J. (2003) Oxidative DNA damage: mechanisms, mutation, and disease. FASEB J. 17,195–1214 </ref> RNAs are likely to be more sensitive to ROS for the following reasons: i) the basically single-stranded structure expose more sites to ROS. ii) compared with nuclear DNA, RNAs are less compartmentalized iii) RNAs distribute broadly in cell not only in nucleus as DNAs do, but also in cytoplasm in large portion. <ref>Li, Z., Wu, J. and Deleo, C.J. (2006) RNA Damage and Surveillance under Oxidative Stress. IUBMB Life, 58(10): 581-588 </ref><ref>Hofer, T., Seo, A. Y., Prudencio, M., and Leeuwenburgh, C. (2006) A method to determine RNA and DNA oxidation simultaneously by [[HPLC-ECD]]: greater RNA than DNA oxidation in rat liver after doxorubicin administration. Biol. Chem. 387, 103 – 111</ref> This theory has been supported by a series of discoveries from rat liver, human [[leukocytes]] and so on. Actually, monitoring system by applying isotopical label [<sup>18</sup>O]-H<sub>2</sub>O<sub>2</sub> shows greater oxidation in cellular RNA than in DNA. Oxidation randomly damages RNAs, each attack would bring problem to the normal cellular metabolism. Although alteration of genetic information on mRNA is relative rare, oxidation on mRNAs [[in vitro]] and [[in vivo]] results in low [[translation]] efficiency and aberrant protein products.<ref>Dukan,S., Farwell, A., Ballesteros, M., Taddei, F., Radman,M. and Nystrom,T. (2000) Protein oxidation in response to increased transcriptional and translational errors. Proc. Natl. Acad. Sci. USA, 97 No.11 5746-5749</ref> Though the [[oxidation]] strikes the nucleic strands randomly, particular residues are more susceptible to ROS and there are such hotspot sites hit by ROS at high rate. Among all the lesions discovered so far, one of the most abundant lesions in DNA and RNA is the 8-hydroxyguanine. <ref>Gajewski, E., Rao, G., Nackerdien, Z., and Dizdaroglu, M. (1990) Modification of DNA bases in mammalian chromatin by radiationgenerated free radicals. Biochemistry 29, 7876 – 7882.</ref> Moreover, 8-hydroxyguanine is the only one measurable among all the RNA lesions. Besides its abundance, 8-hydroxydeoxyguanosine (8-oxodG) and 8-hydroxyguanosine (8-oxoG) are identified as the most detrimental oxidation lesion for its mutagenic effect<ref>Ames, B. N., and Gold, L. S. (1991) Endogenous [[mutagens]] and the causes of aging and cancer. Mutat. Res. 250, 3 – 16.</ref>, which this non-canonical counterpart can faultily pair with both [[adenine]] and [[cytosine]] at the same efficiency.<ref>Shibutani, S., Takeshita, M., and Grollman, A. P. (1991) Insertion of specific bases during DNA synthesis past the oxidation-damaged base 8-oxodG. Nature 349, 431–434.</ref><ref>Taddei, F., Hayakawa, H., Bouton, M., Cirinesi, A., Matic, I., Sekiguchi, M., and Radman, M. (1997) Counteraction by [[MutT]] protein of transcriptional errors caused by oxidative damage. Science 278, 128 – 130.</ref>This mis-pairing brings about the alteration in genetic information through the synthesis of DNA and RNA. In RNA, oxidation levels are mainly estimated through 8-oxoG-based assays. So far, approaches developed for directly measure 8-oxoG level include HPLC-based analysis and assays employing monoclonal anti-8-oxoG antibody. The HPLC-based method measures 8-oxoG by electrochemical detector (ECD) and total G by [[UV]] detector.<ref>Weimann, A., Belling, D., and Poulsen, H. E. (2002) Quantification of 8-oxoGuanine and guanine as the nucleobase, nucleoside and deoxynucleoside forms in human urine by high-performance liquid chromatography-electrospray tandem mass spectrometry. Nucleic Acids Res. 30, E7.</ref> Ratio by comparing the two numbers provides the oxidized extent of total the G .Monoclonal anti-8-oxoG mouse antibody is broadly applied to directly detect this residue either on tissue sections or membrane, offering a more visual way to study its distribution not only in tissues but also in discrete subset of DNA or RNA possible . The established indirect techniques are mainly grounded on this lesion’s mutagenic aftermath. One typical example is lacZ assay.<ref>Park, E. M., Shigenaga, M. K., Degan, P., Korn, T. S., Kitzler, J. W., Wehr, C. M., Kolachana, P., and Ames, B. N. (1992) Assay of excised oxidative DNA lesions: isolation of 8-[[oxoguanine]] and its nucleoside derivatives from biological fluids with a monoclonal antibody column. Proc. Natl. Acad. Sci. USA 89, 3375 – 3379.</ref> This method was firstly set up and described by Taddei and was potentially a powerful tool to understand the oxidation situation both at RNA sequence level and single nucleotide level. Another source of oxidized RNAs is mis-incorporation of oxidized counterpart of single nucleotides. Indeed, the RNA precursor pool size is hundreds size bigger than DNA’s. '''Potential factors for RNA quality control''' There have been furious debates on whether the issue of RNA quality control does exist. However, with the concern of various length of half life of diverse RNA species ranging from several minutes to hours, degradation of defective RNA can not easily be attributed to its transient character anymore. Indeed, reaction with ROS takes only few minutes, which is even shorter than average [[life-span]] of the most unstable RNAs.<ref>Li, Z., Wu, J. and Deleo, C.J. (2006) RNA Damage and Surveillance under Oxidative Stress. IUBMB Life, 58(10): 581-588 </ref> Adding the fact that stable RNA take the lion’s share of total RNA, RNA error deleting become hypercritical and should not be neglected anymore .This theory is upheld by the fact that level of oxidized RNA decreases after removal the oxidative challenge .<ref>Shen, Z., Wu, W., and Hazen, S. L. (2000) Activated leukocytes oxidatively damage DNA, RNA, and the nucleotide pool through halide-dependent formation of hydroxyl radical. Biochemistry 39, 5474 – 5482.</ref><ref>Kajitani, K., Yamaguchi, H., Dan Y., Furuichi, M., Kang D., and Nakabeppu, Y. (2006) MTH1, and oxidized [[purine]] nucleoside triphosphatase, suppresses the accumulation of oxidative damage of nucleic acids in the [[hippocampal]][[ microglia]] during [[kainite]]-induced excitotoxicity. J.Neurosci. 26, 1688-1689.</ref> Some potential facors include [[ribonucleases]], which are suspected to selectively degrade damaged RNAs under stresses. Also [[enzymes]] working at RNA precursor pool level,are known to control quality of RNA sequence by changing error precursor to the form that can't be included directly into nascent strand. == Notes == <references/>