Advances and challenges in identifying and characterizing G-quadruplex–protein interactions

Abstract

Affinity enrichment methods and G-quadruplex (G4) ligand-mediated photo-crosslinking methods can be used to screen new G4-binding proteins (G4BPs) with high throughput and accuracy.Many in vitro methods based on classic nucleic acid–protein interaction assays have been developed to validate G4BPs, but methods for investigating G4–protein interactions within the cellular milieu are still under demand.The development of more highly sensitive, selective, and high-throughput biochemical methods will greatly facilitate the development of G4BP biology. G4s are unique nucleic acid secondary structures formed by stacks of G-tetrads (see Glossary) in DNA or RNA. Through Hoogsteen hydrogen bonds between adjacent G-bases, four G-bases are arranged in a square planar configuration called G-tetrad (Figure 1A) [1.Chen L. et al.DNA G-quadruplex in human telomeres and oncogene promoters: structures, functions, and small molecule targeting.Acc. Chem. Res. 2022; 55: 2628-2646Crossref PubMed Scopus (10) Google Scholar]. The 3D structure formed by stacking two to three layers of G-tetrads is a G4 [2.Bochman M.L. et al.DNA secondary structures: stability and function of G-quadruplex structures.Nat. Rev. Genet. 2012; 13: 770-780Crossref PubMed Scopus (999) Google Scholar]. As numerous G4 structures are present in the genome and transcriptome of living cells, the biological functions of G4s have attracted extensive attention in the past decade [3.Millevoi S. et al.G-quadruplexes in RNA biology.Wiley Interdiscip. Rev. RNA. 2012; 3: 495-507Crossref PubMed Scopus (222) Google Scholar, 4.Rhodes D. Lipps H.J. G-quadruplexes and their regulatory roles in biology.Nucleic Acids Res. 2015; 43: 8627-8637Crossref PubMed Scopus (964) Google Scholar, 5.Fay M.M. et al.RNA G-quadruplexes in biology: principles and molecular mechanisms.J. Mol. 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G-quadruplexes and their regulatory roles in biology.Nucleic Acids Res. 2015; 43: 8627-8637Crossref PubMed Scopus (964) Google D. et al.The regulation and functions of DNA and RNA G-quadruplexes.Nat. Rev. Mol. Cell Biol. 2020; 21: 459-474Crossref PubMed Scopus (438) Google the biological function of a is G4 structure in living has developed a G4 to DNA and RNA G4 in G. et of DNA G-quadruplex structures in human Chem. PubMed Scopus Google G. et and of RNA G-quadruplex structures in the of human Chem. 2014; PubMed Scopus Google Scholar]. G4 have been to G4 structures in living cells et of DNA G-quadruplex in Chem. 2020; 12: PubMed Scopus Google A. et of in Chem. 2015; PubMed Scopus Google S. et of DNA G-quadruplexes in living cells with a Acids Res. 46: PubMed Scopus Google Scholar]. methods important for the of G4 structures in living G4 and high-throughput R. et structures mark human regulatory Genet. 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Cell Biol. 2020; 21: 459-474Crossref PubMed Scopus (438) Google Scholar]. the biological function of a is G4 structure in living has developed a G4 to DNA and RNA G4 in G. et of DNA G-quadruplex structures in human Chem. PubMed Scopus Google G. et and of RNA G-quadruplex structures in the of human Chem. 2014; PubMed Scopus Google Scholar]. G4 have been to G4 structures in living cells et of DNA G-quadruplex in Chem. 2020; 12: PubMed Scopus Google A. et of in Chem. 2015; PubMed Scopus Google S. et of DNA G-quadruplexes in living cells with a Acids Res. 46: PubMed Scopus Google Scholar]. methods important for the of G4 structures in living G4 and high-throughput R. et structures mark human regulatory Genet. 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Commun. 2021; 12: 3885Crossref PubMed Scopus (58) Google J. et al.G-quadruplexes are transcription binding in human Biol. 2021; 22: PubMed Scopus Google Scholar]. the and are to G4 structure but DNA J. et al.G-quadruplexes are transcription binding in human Biol. 2021; 22: PubMed Scopus Google Scholar]. G4BPs to G4s and S. et with nucleic acid and nucleic acid suppresses in cells and in Acids Res. PubMed Scopus Google Scholar] and et to acid in G-quadruplex binding DNA Chem. Biol. 2022; 17: PubMed Scopus Google Scholar, S. et al.The human is a DNA G-quadruplex structure binding and in Acids Res. 2022; PubMed Scopus Google Scholar, S. et DNA and regulate the of G-quadruplex structures in the Sci. S. A. 2020; PubMed Scopus Google Scholar], G4BPs and et and of a Biol. Chem. 2009; Full Text Full Text PDF PubMed Scopus Google Scholar]. G4BPs can and binds G4 and transcription D. et of human is by the in a Biol. 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