Position-Dependent Effect of Guanine Base Damage and Mutations on Telomeric G-Quadruplex and Telomerase Extension

A new synthetic peptide is presented. A Glu residue binds through H-bonding to a guanine-base and a Trp residue intercalates with K+ resulting in stabilization of a human telomeric G-quadruplex with high selectivity over a complementary c-rich strand and double-stranded DNA.

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Guanine-vacancy–bearing G-quadruplexes responsive to guanine derivatives

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1516925112 ◽

2015 ◽

Vol 112 (47) ◽

pp. 14581-14586 ◽

Cited By ~ 58

Author(s):

Xin-min Li ◽

Ke-wei Zheng ◽

Jia-yu Zhang ◽

Hong-he Liu ◽

Yi-de He ◽

...

Keyword(s):

Dimethyl Sulfate ◽

Physiological Concentration ◽

Unique Type ◽

Cellular Processes ◽

G Quadruplex ◽

Guanine Derivatives ◽

Guanine Base ◽

Definition Of ◽

Thermal Melting

G-quadruplex structures formed by guanine-rich nucleic acids are implicated in essential physiological and pathological processes and nanodevices. G-quadruplexes are normally composed of four Gn (n ≥ 3) tracts assembled into a core of multiple stacked G-quartet layers. By dimethyl sulfate footprinting, circular dichroism spectroscopy, thermal melting, and photo-cross-linking, here we describe a unique type of intramolecular G-quadruplex that forms with one G2 and three G3 tracts and bears a guanine vacancy (G-vacancy) in one of the G-quartet layers. The G-vacancy can be filled up by a guanine base from GTP or GMP to complete an intact G-quartet by Hoogsteen hydrogen bonding, resulting in significant G-quadruplex stabilization that can effectively alter DNA replication in vitro at physiological concentration of GTP and Mg2+. A bioinformatic survey shows motifs of such G-quadruplexes are evolutionally selected in genes with unique distribution pattern in both eukaryotic and prokaryotic organisms, implying such G-vacancy–bearing G-quadruplexes are present and play a role in gene regulation. Because guanine derivatives are natural metabolites in cells, the formation of such G-quadruplexes and guanine fill-in (G-fill-in) may grant an environment-responsive regulation in cellular processes. Our findings thus not only expand the sequence definition of G-quadruplex formation, but more importantly, reveal a structural and functional property not seen in the standard canonical G-quadruplexes.

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Guanine base stacking in G-quadruplex nucleic acids

Nucleic Acids Research ◽

10.1093/nar/gks1110 ◽

2012 ◽

Vol 41 (3) ◽

pp. 2034-2046 ◽

Cited By ~ 77

Author(s):

Christopher Jacques Lech ◽

Brahim Heddi ◽

Anh Tuân Phan

Keyword(s):

Nucleic Acids ◽

Base Stacking ◽

G Quadruplex ◽

Guanine Base

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Insights into G-quadruplex specific recognition by the DEAH-box helicase RHAU: Solution structure of a peptide–quadruplex complex

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1422605112 ◽

2015 ◽

Vol 112 (31) ◽

pp. 9608-9613 ◽

Cited By ~ 62

Author(s):

Brahim Heddi ◽

Vee Vee Cheong ◽

Herry Martadinata ◽

Anh Tuân Phan

Keyword(s):

Electrostatic Interactions ◽

Solution Structure ◽

Binding Mode ◽

Structural Basis ◽

Cellular Processes ◽

Charged Amino Acids ◽

G Quadruplex ◽

Guanine Base ◽

Nucleic Acid Structures ◽

Phosphate Groups

Four-stranded nucleic acid structures called G-quadruplexes have been associated with important cellular processes, which should require G-quadruplex–protein interaction. However, the structural basis for specific G-quadruplex recognition by proteins has not been understood. The DEAH (Asp-Glu-Ala-His) box RNA helicase associated with AU-rich element (RHAU) (also named DHX36 or G4R1) specifically binds to and resolves parallel-stranded G-quadruplexes. Here we identified an 18-amino acid G-quadruplex-binding domain of RHAU and determined the structure of this peptide bound to a parallel DNA G-quadruplex. Our structure explains how RHAU specifically recognizes parallel G-quadruplexes. The peptide covers a terminal guanine base tetrad (G-tetrad), and clamps the G-quadruplex using three-anchor-point electrostatic interactions between three positively charged amino acids and negatively charged phosphate groups. This binding mode is strikingly similar to that of most ligands selected for specific G-quadruplex targeting. Binding to an exposed G-tetrad represents a simple and efficient way to specifically target G-quadruplex structures.

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Oxidative guanine base damage regulates human telomerase activity

Nature Structural & Molecular Biology ◽

10.1038/nsmb.3319 ◽

2016 ◽

Vol 23 (12) ◽

pp. 1092-1100 ◽

Cited By ~ 79

Author(s):

Elise Fouquerel ◽

Justin Lormand ◽

Arindam Bose ◽

Hui-Ting Lee ◽

Grace S Kim ◽

...

Keyword(s):

Telomerase Activity ◽

Base Damage ◽

Guanine Base ◽

Human Telomerase

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Water spines and networks in G-quadruplex structures

Nucleic Acids Research ◽

10.1093/nar/gkaa1177 ◽

2020 ◽

Author(s):

Kevin Li ◽

Liliya Yatsunyk ◽

Stephen Neidle

Keyword(s):

Hydrogen Bond ◽

High Resolution ◽

Water Molecule ◽

Crystal Structures ◽

Water Molecules ◽

Nmr Structures ◽

Loop Conformations ◽

G Quadruplex ◽

Guanine Base ◽

Loop Regions

Abstract Quadruplex DNAs can fold into a variety of distinct topologies, depending in part on loop types and orientations of individual strands, as shown by high-resolution crystal and NMR structures. Crystal structures also show associated water molecules. We report here on an analysis of the hydration arrangements around selected folded quadruplex DNAs, which has revealed several prominent features that re-occur in related structures. Many of the primary-sphere water molecules are found in the grooves and loop regions of these structures. At least one groove in anti-parallel and hybrid quadruplex structures is long and narrow and contains an extensive spine of linked primary-sphere water molecules. This spine is analogous to but fundamentally distinct from the well-characterized spine observed in the minor groove of A/T-rich duplex DNA, in that every water molecule in the continuous quadruplex spines makes a direct hydrogen bond contact with groove atoms, principally phosphate oxygen atoms lining groove walls and guanine base nitrogen atoms on the groove floor. By contrast, parallel quadruplexes do not have extended grooves, but primary-sphere water molecules still cluster in them and are especially associated with the loops, helping to stabilize loop conformations.

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The Polarization Dependence of 2D IR Cross-Peaks Distinguishes Parallel-Stranded and Antiparallel-Stranded DNA G-quadruplexes

10.1101/2021.07.13.452271 ◽

2021 ◽

Author(s):

David A Price ◽

Poornima Wedamulla ◽

Tayler D Hill ◽

Taylor M Loth ◽

Sean D. Moran

Keyword(s):

Model Systems ◽

Proximal Promoter ◽

Vibrational Coupling ◽

2D Ir ◽

Wide Range ◽

G Quadruplex ◽

Strand Orientation ◽

Complex Sequences ◽

Guanine Base ◽

Key Features

Guanine-rich nucleic acid sequences have a tendency to form four-stranded non-canonical motifs known as G-quadruplexes. These motifs may adopt a wide range of structures characterized by size, strand orientation, guanine base conformation, and fold topology. Using three K+-bound model systems, we show that vibrational coupling between guanine C6=O and ring modes varies between parallel-stranded and antiparallel-stranded G-quadruplexes, and that such structures can be distinguished by comparison of polarization dependent cross-peaks in their two-dimensional infrared (2D IR) spectra. Combined with previously defined vibrational frequency trends, this analysis reveals key features of a 30-nucleotide unimolecular variant of the Bcl-2 proximal promoter that are consistent with its reported structure. This study shows that 2D IR spectroscopy is a convenient method for analyzing G-quadruplex structures that can be applied to complex sequences where traditional high-resolution methods are limited by solubility and disorder.

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A Novel G-Quadruplex Binding Protein in Yeast—Slx9

Molecules ◽

10.3390/molecules24091774 ◽

2019 ◽

Vol 24 (9) ◽

pp. 1774 ◽

Cited By ~ 6

Author(s):

Silvia Götz ◽

Satyaprakash Pandey ◽

Sabrina Bartsch ◽

Stefan Juranek ◽

Katrin Paeschke

Keyword(s):

Binding Protein ◽

Sequence Motifs ◽

Dna And Rna ◽

G4 Dna ◽

G Quadruplex ◽

High Thermodynamic Stability ◽

Guanine Base ◽

Regulatory Functions

G-quadruplex (G4) structures are highly stable four-stranded DNA and RNA secondary structures held together by non-canonical guanine base pairs. G4 sequence motifs are enriched at specific sites in eukaryotic genomes, suggesting regulatory functions of G4 structures during different biological processes. Considering the high thermodynamic stability of G4 structures, various proteins are necessary for G4 structure formation and unwinding. In a yeast one-hybrid screen, we identified Slx9 as a novel G4-binding protein. We confirmed that Slx9 binds to G4 DNA structures in vitro. Despite these findings, Slx9 binds only insignificantly to G-rich/G4 regions in Saccharomyces cerevisiae as demonstrated by genome-wide ChIP-seq analysis. However, Slx9 binding to G4s is significantly increased in the absence of Sgs1, a RecQ helicase that regulates G4 structures. Different genetic and molecular analyses allowed us to propose a model in which Slx9 recognizes and protects stabilized G4 structures in vivo.

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