G4-quadruplex-binding proteins: review and insights into selectivity

Abstract

There are over 700,000 putative G4-quadruplexes (G4Qs) in the human genome, found largely in promoter regions, telomeres, and other regions of high regulation. Growing evidence links their presence to functionality in various cellular processes, where cellular proteins interact with them, either stabilizing and/or anchoring upon them, or unwinding them to allow a process to proceed. Interest in understanding and manipulating the plethora of processes regulated by these G4Qs has spawned a new area of small-molecule binder development, with attempts to mimic and block the associated G4-binding protein (G4BP). Despite the growing interest and focus on these G4Qs, there is limited data (in particular, high-resolution structural information), on the nature of these G4Q-G4BP interactions and what makes a G4BP selective to certain G4Qs, if in fact they are at all. This review summarizes the current literature on G4BPs with regards to their interactions with G4Qs, providing groupings for binding mode, drawing conclusions around commonalities and highlighting information on specific interactions where available.

Interactions of small molecules with DNA junctions

“…and the proteins associated combining both sequencing (bioinformatic tools will have to be optimized as well) and proteomics. Of note, the identification of DNA junction-binding proteins will be a very important step as they are the cellular effectors by which the response to junction stabilization by ad hoc ligands is mediated; while hundreds of G4-binding proteins are now known ( 215 ), only a handful of junction-binding proteins have been reported to date (e.g. RuvABC and RecG, vide supra ); (iv) produce DNA junction-specific antibodies for both immunoprecipitation and immunodetection purposes, and (v) develop cellular and small animal models to assess the properties of identified candidates in a standardized manner.…”

DNA Base Excision Repair Intermediates Influence Duplex–Quadruplex Equilibrium

“…Thus, the cytotoxicity of pyridostatin may be attributed to stabilizing existing quadruplexes but also trapping the quadruplex configuration in the apparently hundreds of thousands of quadruplex-forming regions that are in equilibrium with duplex [ 6 ]. Furthermore, the duplex–quadruplex equilibrium may similarly be influenced and regulated by the presence of quadruplex-binding enzymes [ 29 , 36 , 45 , 46 , 47 ].…”

Understanding the Interactions of Guanine Quadruplexes with Peptides as Novel Strategies for Diagnosis or Tuning Biological Functions

“…Peptides can also bind RNA quadruplexes that recently emerged as excellent target both in human and non-human genomes. [55] C9orf72 (C9) is the gene responsible for the familial form of amyotrophic lateral sclerosis (ALS) and related frontotemporal dementia (FTD). This familial form is due to a hexanucleotide repeat expansion (HRE) of (GGGGCC), inclined to form a G4 structure.…”

“…Still, the interaction between G4s and proteins is an important area of research which deserves attention as witnessed from a recent excellent review. [55] Because of these intrinsic limitations, understanding the recognition of particular G4s by specific peptides could be invaluable from a pharmacological or biotechnological point of view. Indeed, such specificity might lead on the one side to the development of highly sensitive G4 ligands, which could potentially be used as therapeutics but also for noninvasive diagnostic purposes as biomarkers for specific diseases.…”