5,6-Saturated thymine lesions in DNA: production by ultraviolet light or hydrogen peroxide

Demple, Bruce; Linn, Stuart

doi:10.1093/nar/10.12.3781

Cited by 128 publications

(59 citation statements)

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“…Thymine glycol in DNA can be excised in vitro by Escherichia coli endonuclease III or other enzymes, which liberates the thymine glycol and subsequently carries out a ␤-elimination reaction to cleave the 3Ј phosphodiester as was first shown by Demple and Linn (17,18). We have shown that endo 1 III cleaves the 3Ј phosphodiester of abasic sites via a syn ␤-elimination reaction (17)(18)(19)(20).…”

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confidence: 74%

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Structure of a Duplex DNA Containing a Thymine Glycol Residue in Solution

Kung

Bolton

1997

Journal of Biological Chemistry

105

114

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Oxidative stress, ionizing radiation, and other events can induce the oxidation of the thymine in DNA to thymine glycol. The presence of thymine glycol can have significant biological consequences, and there are specific repair enzymes for thymine glycol in a wide range of organisms. The structure of a duplex DNA containing a single thymine glycol (5,6-dihydroxy-5,6-dihydrothymidine) has been determined by the combined use of NMR and restrained molecular dynamics. The duplex of d(C 1 G 2 C 3 G 4 A 5 Tg 6 A 7 C 8 G 9 C 10 C 11 ) paired with d(G 22 C 21 G 20 -C 19 T 18 A 17 T 16 G 15 C 14 G 13 G 12 ), with Tg indicating thymine glycol, has been used for these studies. The structure shows that the thymine glycol induces a significant, localized structural change with the thymine glycol largely extrahelical. This structural information is consistent with the biological consequences of thymine glycol in DNA. This structure is compared with that of a DNA duplex with an abasic site in the same sequence context.Damage to DNA can occur by the spontaneous deamination of cytosine to uracil and through the action of alkylating agents, oxidants, drugs, and toxins, ionizing radiation, and other modes of action (1-3). The exposure of DNA in cells bound to proteins as a solid or free in solution to ionizing radiation or to oxidative stress can lead to the conversion of thymine to thymine glycol (5,6-dihydroxy-5,6-dihydrothymidine). Approximately 10 -20% of the damage to DNA induced by ionizing radiation, including that used to treat tumors, is the result of thymine base oxidation and fragmentation. These products can also be produced by oxidative stress. In addition, the importance of damaged DNA as a control on the cell cycle is increasingly becoming a focus of research efforts so that the effects of damaged thymines on the structures, stabilities, dynamics, and interactions of DNA are of interest.It has been known for several decades that ionizing radiation can stop the reproduction of cells as well as kill cells. These activities form the basis for using radiation in chemotherapy, and the research in this area has been frequently reviewed (1-13). Since the mid-1950s there have been studies on the effects of ionizing radiation on the chemical integrity of DNA (4,5,7,9, 14). Ionizing radiation can induce a number of types of damage to DNA including single and double strand breaks, oxidation of the purine and pyrimidine bases, and cross-linking of DNA with proteins. Radiation-generated oxidants are thought to react with thymine to lead to the formation of thymine glycol, thymine peroxide, thymine hydroperoxide, and other oxidized forms of the base. Some of these oxidized forms of thymine subsequently react further to form urea. Some of the same types of damage also occurs to DNA during oxidative stress (5,15,16).The damage to the thymine bases in DNA is of special interest because the major forms of damaged thymine are known; thymine is the most easily oxidized base, and many of the biological consequences of damaged thymines a...

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“…We have shown that endo 1 III cleaves the 3Ј phosphodiester of abasic sites via a syn ␤-elimination reaction (17)(18)(19)(20). A mammalian homolog of endo III has recently been found (21).…”

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Structure of a Duplex DNA Containing a Thymine Glycol Residue in Solution

Kung

Bolton

1997

Journal of Biological Chemistry

105

114

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“…Although H 2 O 2 can produce DNA strand breaks with low efficiency (Demple and Linn, 1982), the repair of UV lesions by the action of the uvr gene products generated single-stranded DNA regions and it was supposed that, in the presence of H 2 O 2 , DNA double-strand breaks might arise in these regions, produced by the action of exonuclease III (the xthA gene product). This hypothesis was confirmed by the absence of synergistic lethal interaction between UV (254 nm) and H 2 O 2 in xthA as well as in uvrA mutant strains (Leitão and Carvalho, 1988).…”

Section: Lethal Synergism Between Uv (254 Nm) and H 2 Omentioning

confidence: 99%

Several pathways of hydrogen peroxide action that damage the E. coli genome

Asad

Almeida

et al. 2004

Genet. Mol. Biol.

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Hydrogen peroxide is an important reactive oxygen species (ROS) that arises either during the aerobic respiration process or as a by-product of water radiolysis after exposure to ionizing radiation. The reaction of hydrogen peroxide with transition metals imposes on cells an oxidative stress condition that can result in damage to cell components such as proteins, lipids and principally to DNA, leading to mutagenesis and cell death. Escherichia coli cells are able to deal with these adverse events via DNA repair mechanisms, which enable them to recover their genome integrity. These include base excision repair (BER), nucleotide excision repair (NER) and recombinational repair. Other important defense mechanisms present in Escherichia coli are OxyR and SosRS anti-oxidant inducible pathways, which are elicited by cells to avoid the introduction of oxidative lesions by hydrogen peroxide. This review summarizes the phenomena of lethal synergism between UV irradiation (254 nm) and H 2 O 2 , the cross-adaptive response between different classes of genotoxic agents and hydrogen peroxide, and the role of copper ions in the lethal response to H 2 O 2 under low-iron conditions. Key words: hydrogen peroxide, cross-adaptive response, lethal synergism, copper and iron. General AspectsThe appearance of aerobic forms of life was an important step in the evolutionary process, since oxygen consumption leads to the production of ten-fold more energy from glucose than does anaerobic metabolism (Meneghini, 1987). However, this process imposes constraints on cell viability, because of the generation of reactive oxygen species during respiration.The consecutive univalent reduction of molecular oxygen to water produces three active intermediates: superoxide anion (O 2 -• ), hydrogen peroxide (H 2 O 2 ) and hydroxyl radical (OH • ). These intermediates, collectively referred to as reactive oxygen species (ROS) are potent oxidants of lipids, proteins, and nucleic acids (Halliwell and Gutteridge, 1984;Mello-Filho and Meneghini, 1985;Meneghini, 1988). Among the oxidative DNA lesions, one of the major classes of DNA damage leads to modification in purine and pyrimidine bases, together with oligonucleotide strand breaks, DNA-protein cross-links and abasic sites. Increasing evidence suggests that the cumulative damage caused by ROS contributes to numerous degenerative diseases associated with aging, such as atherosclerosis, rheumatoid arthritis and cancer (Ames et al., 1993;Halliwell and Gutteridge, 1999).Living organisms have developed specific mechanisms to prevent the production and effects of ROS. The reduction of O 2 by cytochrome oxidase without yielding ROS, the superoxide dismutase catalysis of O 2 -• into H 2 O 2 through a dismutation reaction, the decomposition of H 2 O 2 by catalase and peroxidases, and the scavenging of ROS by some vitamins comprise part of the set of cellular antioxidant defenses (Halliwell and Gutteridge, 1999). Synthesis of the enzymes that catalyze these reactions is a part of the adaptive response tr...

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“…These lesions are also generated by intracellular reactive oxygen species (ROS). A highly conserved enzyme acting on DNA containing deaminated bases was first identified by Gates and Linn (9) in Escherichia coli as the product of nfi gene and is called endonuclease V. Endonuclease V is a magnesium-dependent endonuclease that makes a nick at the second phosphodiester bond 3Ј to the substrate lesion, leaving 3Ј-OH and 5Ј-P termini (10). It is suspected that a 3Ј-5Ј exonuclease activity followed by DNA polymerase and DNA ligase activities would then complete the repair.…”

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A bifunctional DNA repair protein from Ferroplasma acidarmanus exhibits O ⁶ -alkylguanine-DNA alkyltransferase and endonuclease V activities

Kanugula

Pauly

Moschel

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

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A recently discovered DNA repair protein of 303 aa from the archaeal organism Ferroplasma acidarmanus was studied. This protein (AGTendoV) consists of a fusion of the C-terminal active site domain of O 6 -alkylguanine-DNA alkyltransferase (AGT) with an endonuclease V domain. The AGTendoV recombinant protein expressed in Escherichia coli and purified to homogeneity repaired O 6 -methylguanine lesions in DNA via alkyl transfer action despite the complete absence of the N-terminal domain and some differences in key active site residues present in known AGTs. The AGTendoV recombinant protein also cleaved DNA substrates that contained the deaminated bases uracil, hypoxanthine, or xanthine in a similar manner to E. coli endonuclease V. Expression of AGTendoV in E. coli GWR109, a strain that lacks endogenous AGT activity, protected against both the killing and mutagenic activity of N-methyl-N -nitro-N-nitrosoguanidine and was more effective in preventing mutations than human alkyltransferase, suggesting that the endonuclease V activity may also repair a promutagenic lesion produced by this alkylating agent. Expression of AGTendoV in a DNA repair-deficient E. coli nfi ؊ alkA ؊ strain protected from spontaneous mutations arising in saturated cultures and restored the mutation frequency to that found in the nfi ؉ alkA ؉ strain. These results demonstrate the physiological occurrence of two completely different but functional DNA repair activities in a single polypeptide chain. deamination ͉ genotoxicity ͉ alkylationA GT (O 6 -alkylguanine-DNA alkyltransferase) is a DNA repair protein that removes alkyl adducts from the O 6 -position of guanine and O 4 -position of thymine in DNA (1, 2). If they are not removed, these lesions are highly mutagenic and carcinogenic (1,3,4). AGTs repair these DNA adducts by transferring the alkyl group onto a cysteine amino acid residue at the active site of the protein, thus restoring the DNA to its unmodified form in a single step. This alkyl transfer reaction permanently inactivates the AGT, and synthesis of new protein is required for further repair of the DNA damage. The presence of a characterized AGT gene product or a putative gene coding for the protein has been reported so far in Ͼ100 different species from the three domains of life, Archaea, Bacteria, and Eukarya. However, it is not ubiquitous: it is apparently absent from plants, Schizosaccharomyces pombe, and Deinococcus radiodurans. The AGT proteins share a highly conserved -PCHRV-amino acid sequence in their active site and contain a number of other conserved amino acids in the active site and DNA-binding domain of the protein. The widespread presence of AGT indicates the occurrence of alkylation damage to DNA under a variety of living conditions and the need to repair such damage in the cell. Alkylating agents including N-nitroso compounds are present in the environment and can be generated endogenously.Crystal structures for AGT from three different species (Escherichia coli, human, and Pyrococcus kodakaraensis) have been deter...

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5,6-Saturated thymine lesions in DNA: production by ultraviolet light or hydrogen peroxide

Cited by 128 publications

References 20 publications

Structure of a Duplex DNA Containing a Thymine Glycol Residue in Solution

Structure of a Duplex DNA Containing a Thymine Glycol Residue in Solution

Several pathways of hydrogen peroxide action that damage the E. coli genome

A bifunctional DNA repair protein from Ferroplasma acidarmanus exhibits O ⁶ -alkylguanine-DNA alkyltransferase and endonuclease V activities

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5,6-Saturated thymine lesions in DNA: production by ultraviolet light or hydrogen peroxide

Cited by 128 publications

References 20 publications

Structure of a Duplex DNA Containing a Thymine Glycol Residue in Solution

Structure of a Duplex DNA Containing a Thymine Glycol Residue in Solution

Several pathways of hydrogen peroxide action that damage the E. coli genome

A bifunctional DNA repair protein from Ferroplasma acidarmanus exhibits O 6 -alkylguanine-DNA alkyltransferase and endonuclease V activities

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Product

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A bifunctional DNA repair protein from Ferroplasma acidarmanus exhibits O ⁶ -alkylguanine-DNA alkyltransferase and endonuclease V activities