Constrained G4 structures unveil topology specificity of known and new G4 binding proteins

Pipier, Angélique; Devaux, Alexandre; Lavergne, Thomas; Adrait, Annie; Couté, Yohann; Britton, Sébastien; Calsou, Patrick; Riou, Jean‐François; Defrancq, Éric; Gómez, Dennis

doi:10.1101/2021.04.06.438633

Cited by 3 publications

(3 citation statements)

References 81 publications

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“…End-resection is one of the first steps during HR that is mainly mediated by exonuclease 1 (EXO1) [105]. It has been shown in human cells that EXO1 is important for replication and resection near G4 structures [69].…”

Section: Pathwaymentioning

confidence: 99%

The Relevance of G-Quadruplexes for DNA Repair

Linke

Limmer

Juranek

et al. 2021

IJMS

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DNA molecules can adopt a variety of alternative structures. Among these structures are G-quadruplex DNA structures (G4s), which support cellular function by affecting transcription, translation, and telomere maintenance. These structures can also induce genome instability by stalling replication, increasing DNA damage, and recombination events. G-quadruplex-driven genome instability is connected to tumorigenesis and other genetic disorders. In recent years, the connection between genome stability, DNA repair and G4 formation was further underlined by the identification of multiple DNA repair proteins and ligands which bind and stabilize said G4 structures to block specific DNA repair pathways. The relevance of G4s for different DNA repair pathways is complex and depends on the repair pathway itself. G4 structures can induce DNA damage and block efficient DNA repair, but they can also support the activity and function of certain repair pathways. In this review, we highlight the roles and consequences of G4 DNA structures for DNA repair initiation, processing, and the efficiency of various DNA repair pathways.

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Section: Pathwaymentioning

confidence: 99%

The Relevance of G-Quadruplexes for DNA Repair

Linke

Limmer

Juranek

et al. 2021

IJMS

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“…The 425 G4 interacting proteins recently identified using probes containing various constrained G4 structures are enriched for spliceosomes, RNA transport, RNA degradation, mRNA surveillance, DNA replication, and homologous recombination pathways. One G4-binding protein complex, the negative elongation factor (NELF), regulates gene expression in eukaryotic cells by promoting RNA polymerase pausing [ 62 ]. Other cell-based studies demonstrate the presence of nuclear G4 structures [ 63 , 64 ].…”

Section: G-fliponsmentioning

confidence: 99%

The Simple Biology of Flipons and Condensates Enhances the Evolution of Complexity

Herbert

2021

Molecules

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The classical genetic code maps nucleotide triplets to amino acids. The associated sequence composition is complex, representing many elaborations during evolution of form and function. Other genomic elements code for the expression and processing of RNA transcripts. However, over 50% of the human genome consists of widely dispersed repetitive sequences. Among these are simple sequence repeats (SSRs), representing a class of flipons, that under physiological conditions, form alternative nucleic acid conformations such as Z-DNA, G4 quartets, I-motifs, and triplexes. Proteins that bind in a structure-specific manner enable the seeding of condensates with the potential to regulate a wide range of biological processes. SSRs also encode the low complexity peptide repeats to patch condensates together, increasing the number of combinations possible. In situations where SSRs are transcribed, SSR-specific, single-stranded binding proteins may further impact condensate formation. Jointly, flipons and patches speed evolution by enhancing the functionality of condensates. Here, the focus is on the selection of SSR flipons and peptide patches that solve for survival under a wide range of environmental contexts, generating complexity with simple parts.

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“…A possible remedy to mimic the tetrameric simulation model might come from the utilization of GQs constrained by an additional structural element serving as a scaffold, such as Holliday junction 160 or an oligopeptide. 161…”

Section: ■ Discussionmentioning

confidence: 99%

Mechanical Stability and Unfolding Pathways of Parallel Tetrameric G-Quadruplexes Probed by Pulling Simulations

Zhang,

Mlýnský,

Krepl

et al. 2024

J. Chem. Inf. Model.

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Guanine quadruplex (GQ) is a noncanonical nucleic acid structure formed by guanine-rich DNA and RNA sequences. Folding of GQs is a complex process, where several aspects remain elusive, despite being important for understanding structure formation and biological functions of GQs. Pulling experiments are a common tool for acquiring insights into the folding landscape of GQs. Herein, we applied a computational pulling strategy�steered molecular dynamics (SMD) simulations�in combination with standard molecular dynamics (MD) simulations to explore the unfolding landscapes of tetrameric parallel GQs. We identified anisotropic properties of elastic conformational changes, unfolding transitions, and GQ mechanical stabilities. Using a special set of structural parameters, we found that the vertical component of pulling force (perpendicular to the average G-quartet plane) plays a significant role in disrupting GQ structures and weakening their mechanical stabilities. We demonstrated that the magnitude of the vertical force component depends on the pulling anchor positions and the number of G-quartets. Typical unfolding transitions for tetrameric parallel GQs involve base unzipping, opening of the G-stem, strand slippage, and rotation to cross-like structures. The unzipping was detected as the first and dominant unfolding event, and it usually started at the 3′-end. Furthermore, results from both SMD and standard MD simulations indicate that partial spiral conformations serve as a transient ensemble during the (un)folding of GQs.

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Constrained G4 structures unveil topology specificity of known and new G4 binding proteins

Cited by 3 publications

References 81 publications

The Relevance of G-Quadruplexes for DNA Repair

The Relevance of G-Quadruplexes for DNA Repair

The Simple Biology of Flipons and Condensates Enhances the Evolution of Complexity

Mechanical Stability and Unfolding Pathways of Parallel Tetrameric G-Quadruplexes Probed by Pulling Simulations

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