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Interplay of Guanine Oxidation and G-Quadruplex Folding in Gene Promoters.

ABSTRACT: Living in an oxygen atmosphere demands an ability to thrive in the presence of reactive oxygen species (ROS). Aerobic organisms have successfully found solutions to the oxidative threats imposed by ROS by evolving an elaborate detoxification system, upregulating ROS during inflammation, and utilizing ROS as messenger molecules. In this Perspective, recent studies are discussed that demonstrate ROS as signaling molecules for gene regulation by combining two emergent properties of the guanine (G) heterocycle in DNA, namely, oxidation sensitivity and a propensity for G-quadruplex (G4) folding, both of which depend upon sequence context. In human gene promoters, this results from an elevated 5'-GG-3' dinucleotide frequency and GC enrichment near transcription start sites. Oxidation of DNA by ROS drives conversion of G to 8-oxo-7,8-dihydroguanine (OG) to mark target promoters for base excision repair initiated by OG-glycosylase I (OGG1). Sequence-dependent mechanisms for gene activation are available to OGG1 to induce transcription. Either OGG1 releases OG to yield an abasic site driving formation of a non-canonical fold, such as a G4, to be displayed to apurinic/apyrimidinic 1 (APE1) and stalling on the fold to recruit activating factors, or OGG1 binds OG and facilitates activator protein recruitment. The mechanisms described drive induction of stress response, DNA repair, or estrogen-induced genes, and these pathways are novel potential anticancer targets for therapeutic intervention. Chemical concepts provide a framework to discuss the regulatory or possible epigenetic potential of the OG modification in DNA, in which DNA "damage" and non-canonical folds collaborate to turn on or off gene expression. The next steps for scientific discovery in this growing field are discussed.

SUBMITTER: Fleming AM

PROVIDER: S-EPMC6988379 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature

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Interplay of Guanine Oxidation and G-Quadruplex Folding in Gene Promoters.

Fleming Aaron M AM Burrows Cynthia J CJ

Journal of the American Chemical Society 20200109 3

Living in an oxygen atmosphere demands an ability to thrive in the presence of reactive oxygen species (ROS). Aerobic organisms have successfully found solutions to the oxidative threats imposed by ROS by evolving an elaborate detoxification system, upregulating ROS during inflammation, and utilizing ROS as messenger molecules. In this Perspective, recent studies are discussed that demonstrate ROS as signaling molecules for gene regulation by combining two emergent properties of the guanine (G) ...[more]

PMID: 31880930

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Project description:Telomere shortening occurs during oxidative and inflammatory stress with guanine (G) as the major site of damage. In this work, a comprehensive profile of the sites of oxidation and structures of products observed from G-quadruplex and duplex structures of the human telomere sequence was studied in the G-quadruplex folds (hybrid (K(+)), basket (Na(+)), and propeller (K(+) + 50% CH3CN)) resulting from the sequence 5'-(TAGGGT)4T-3' and in an appropriate duplex containing one telomere repeat. Oxidations with four oxidant systems consisting of riboflavin photosensitization, carbonate radical generation, singlet oxygen, and the copper Fenton-like reaction were analyzed under conditions of low product conversion to determine relative reactivity. The one-electron oxidants damaged the 5'-G in G-quadruplexes leading to spiroiminodihydantoin (Sp) and 2,2,4-triamino-2H-oxazol-5-one (Z) as major products as well as 8-oxo-7,8-dihydroguanine (OG) and 5-guanidinohydantoin (Gh) in low relative yields, while oxidation in the duplex context produced damage at the 5'- and middle-Gs of GGG sequences and resulted in Gh being the major product. Addition of the reductant N-acetylcysteine (NAC) to the reaction did not alter the riboflavin-mediated damage sites but decreased Z by 2-fold and increased OG by 5-fold, while not altering the hydantoin ratio. However, NAC completely quenched the CO3(•-) reactions. Singlet oxygen oxidations of the G-quadruplex showed reactivity at all Gs on the exterior faces of G-quartets and furnished the product Sp, while no oxidation was observed in the duplex context under these conditions, and addition of NAC had no effect. Because a long telomere sequence would have higher-order structures of G-quadruplexes, studies were also conducted with 5'-(TAGGGT)8-T-3', and it provided oxidation profiles similar to those of the single G-quadruplex. Lastly, Cu(II)/H2O2-mediated oxidations were found to be indiscriminate in the damage patterns, and 5-carboxamido-5-formamido-2-iminohydantoin (2Ih) was found to be a major duplex product, while nearly equal yields of 2Ih and Sp were observed in G-quadruplex contexts. These findings indicate that the nature of the secondary structure of folded DNA greatly alters both the reactivity of G toward oxidative stress as well as the product outcome and suggest that recognition of damage in telomeric sequences by repair enzymes may be profoundly different from that of B-form duplex DNA.

Dataset Information

Interplay of Guanine Oxidation and G-Quadruplex Folding in Gene Promoters.

Publications

Interplay of Guanine Oxidation and G-Quadruplex Folding in Gene Promoters.

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