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DNA Damage and Repair in G-Quadruplexes Impact Gene Expression

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Handbook of Chemical Biology of Nucleic Acids

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Abstract

Guanine-rich sequences in DNA are sensitive to oxidation to 8-oxo-7,8-dihydroguanine (OG) during cellular oxidative stress. When this base modification occurs in a sequence capable of refolding from a canonical duplex DNA structure to a G-quadruplex (G4) in a gene-regulatory region of the genome, modulation of gene expression can occur. The cellular reader of OG in humans is OGG1, a DNA glycosylase of the base excision repair pathway which is followed by the activity of apurinic/apyrimidinic endonuclease-1 (APE1) to cleave the 5′ phosphodiester bond adjacent to the abasic site. However, APE1’s cleavage activity is severely attenuated in the G4 context, and DNA binding of the protein instead leads to the recruitment of activating transcription factors when the G4 is located in the nontemplate strand of a promoter close to the transcription start site. In this chapter, we present structural and mechanistic studies pertinent to the APE1-mediated modulation of gene expression under oxidative conditions and briefly cover related mechanisms stemming only from the activity of OGG1; the latter examples do not necessarily involve G-quadruplex formation. Finally, we present a future outlook with unanswered questions.

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Acknowledgments

Research on this topic in our laboratory was supported by grants from the US National Institutes of Health, including R01 CA090689, R01 GM129267, and presently R35 GM145237.

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  1. Department of Chemistry, University of Utah, Salt Lake City, UT, USA

    Aaron M. Fleming & Cynthia J. Burrows

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  1. Aaron M. Fleming
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  2. Cynthia J. Burrows
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Correspondence to Cynthia J. Burrows .

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  1. Frontier Institute for Biomolecular Engineering Research (FIBER), Konan University, Kobe, Japan

    Naoki Sugimoto

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  1. University of Utah, Salt Lake City, USA

    Cynthia J. Burrows

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Fleming, A.M., Burrows, C.J. (2023). DNA Damage and Repair in G-Quadruplexes Impact Gene Expression. In: Sugimoto, N. (eds) Handbook of Chemical Biology of Nucleic Acids. Springer, Singapore. https://doi.org/10.1007/978-981-16-1313-5_38-1

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  • DOI: https://doi.org/10.1007/978-981-16-1313-5_38-1

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