Sequence dependence for bypass of thymine glycols in DNA by DNA polymerase I

Hayes, Robert C.; LeClerc, J E

doi:10.1093/nar/14.2.1045

Cited by 105 publications

(81 citation statements)

References 26 publications

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“…Several groups have now established that ring-saturated thymine lesions are non-coding rather than miscoding (Hariharan et al, 1977;Ide et al, 1985;Rouet & Essingmann, 1985;Clark & Beardsley, 1986;Hayes & Le Clerk, 1986). DNA templates have been oxidized to yield thymine glycols or further, unspecified, breakdown products (possibly urea).…”

Section: Dna Lesions and Their Repairmentioning

confidence: 99%

Ionizing radiation-induced mutagenesis

Breimer

1988

Br J Cancer

149

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Section: Dna Lesions and Their Repairmentioning

confidence: 99%

Ionizing radiation-induced mutagenesis

Breimer

1988

Br J Cancer

149

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“…Even though there are DNA repair enzymes specialized in excising Tg from the genome, such as human NEIL1 and NTH1 (6)(7)(8), statistically a few of the damaged bases will evade repair, which means that DNA polymerases will encounter these lesions during replication. Although Tg is a poor mutagenic lesion because it generally pairs with A (9), it has been shown to be a very effective block to DNA replication (10)(11)(12)(13). When Tg is encountered as a templating base by replicative or repair polymerases, termination of primer extension occurs immediately past the lesion site with A inserted opposite the Tg.…”

mentioning

confidence: 99%

A structural rationale for stalling of a replicative DNA polymerase at the most common oxidative thymine lesion, thymine glycol

Aller

Rould

Hogg³

et al. 2007

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

133

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Thymine glycol (Tg) is a common product of oxidation and ionizing radiation, including that used for cancer treatment. Although Tg is a poor mutagenic lesion, it has been shown to present a strong block to both repair and replicative DNA polymerases. The 2.65-Å crystal structure of a binary complex of the replicative RB69 DNA polymerase with DNA shows that the templating Tg is intrahelical and forms a regular Watson-Crick base pair with the incorporated A. The C5 methyl group protrudes axially from the ring of the damaged pyrimidine and hinders stacking of the adjacent 5 template guanine. The position of the displaced 5 template guanine is such that the next incoming nucleotide cannot be incorporated into the growing primer strand, and it explains why primer extension past the lesion is prohibited even though DNA polymerases can readily incorporate an A across from the Tg lesion.oxidative DNA damage ͉ structure ͉ DNA replication T hymine glycol (5,6-dihydro-5,6-dihydroxythymine; Tg), the most common oxidation product of thymine, is produced endogenously as a consequence of aerobic metabolism or via exogenous factors such as chemical oxidants or ionizing radiation (Fig. 1). It is estimated that 400 Tgs are formed per cell per day (1, 2), and the presence of Tg in DNA has been used as a marker for oxidative stress (1, 3). Moreover, Tg is one of the predominant types of base modifications produced by ionizing radiation (4, 5), including that used in cancer therapy.Of the oxidatively modified DNA bases retaining an intact ring, Tg is thought to induce the most distortion in the regular structure of DNA. Even though there are DNA repair enzymes specialized in excising Tg from the genome, such as human , statistically a few of the damaged bases will evade repair, which means that DNA polymerases will encounter these lesions during replication. Although Tg is a poor mutagenic lesion because it generally pairs with A (9), it has been shown to be a very effective block to DNA replication (10-13). When Tg is encountered as a templating base by replicative or repair polymerases, termination of primer extension occurs immediately past the lesion site with A inserted opposite the Tg. Even in the presence of proofreading, extension proceeds no further. This finding contrasts with the situation observed when the lesion is an abasic site, where, in the presence of proofreading, termination sites are observed one base before the lesion (14). Therefore, it is extension past the Tg⅐adenine pair, rather than insertion across Tg, that constitutes the block to the replicative polymerases. Because Tg is a strong block to repair and replicative DNA polymerases in vitro (10-13), not surprisingly, it is a lethal lesion in vivo (9,(15)(16)(17)(18).Unlike normal DNA bases, Tg is nonplanar because of the loss of aromatic character that accompanies the addition of hydroxyl groups at the 5 and 6 positions of the ring (19). Computational simulations (20,21) predict that the axial orientation of the methyl group with respect to the pyrimidine r...

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“…Thus, there may be as many as three routes to thymine glycol repair: endo III; exonuclease III and endo IV; and SOS (13). These results indicate that thymine glycol sites can be repaired in vivo in organisms ranging from E. coli to mammals.The presence of thymine glycol in DNA can have profound consequences on DNA replication (9,13,(23)(24)(25)(26)(27). The presence of thymine glycol is a block to replication (23-28).…”

mentioning

confidence: 99%

“…The presence of thymine glycol in DNA can have profound consequences on DNA replication (9,13,(23)(24)(25)(26)(27). The presence of thymine glycol is a block to replication (23)(24)(25)(26)(27)(28).…”

mentioning

confidence: 99%

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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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Sequence dependence for bypass of thymine glycols in DNA by DNA polymerase I

Cited by 105 publications

References 26 publications

Ionizing radiation-induced mutagenesis

Ionizing radiation-induced mutagenesis

A structural rationale for stalling of a replicative DNA polymerase at the most common oxidative thymine lesion, thymine glycol

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

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