ArticleNucleic acids research2020
Human POT1 unfolds G-quadruplexes by conformational selection.
Article in Nucleic acids research, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 22 papers.
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Who cites it
22 citing papers in PubMed, 38 citations in OpenAlex.
- Unwinding process of DNA/RNA quadruplexes by proteins under label-free nanopore monitoring.Nucleic acids research · 2025Article
- Protein G-quadruplex interactions and their effects on phase transitions and protein aggregation.Nucleic acids research · 2024Article
- Protein G-quadruplex interactions and their effects on phase transitions and protein aggregation.bioRxiv : the preprint server for biology · 2024Article
- Guardians of the Genome: How the Single-Stranded DNA-Binding Proteins RPA and CST Facilitate Telomere Replication.Biomolecules · 2024Review
- RPA engages telomeric G-quadruplexes more effectively than CST.Nucleic acids research · 2023Article
- G-quadruplexes and associated proteins in aging and Alzheimer's disease.Frontiers in aging · 2023Review
- Shelterin reduces the accessibility of telomeric overhangs.Nucleic acids research · 2022Article
- Targeting telomeres: advances in telomere maintenance mechanism-specific cancer therapies.Nature reviews. Cancer · 2022Review
- Telomere dysfunction implicates POT1 in patients with idiopathic pulmonary fibrosis.The Journal of experimental medicine · 2022Article
- G-Quadruplex-Binding Proteins: Promising Targets for Drug Design.Biomolecules · 2022Review
- Telomere Targeting Approaches in Cancer: Beyond Length Maintenance.International journal of molecular sciences · 2022Review
- Insights into POT1 structural dynamics revealed by cryo-EM.PloS one · 2022Article
- Multiple hPOT1-TPP1 cooperatively unfold contiguous telomeric G-quadruplexes proceeding from 3' toward 5', a feature due to a 3'-end binding preference and to structuring of telomeric DNA.Nucleic acids research · 2021Article
- G-quadruplex DNA: a novel target for drug design.Cellular and molecular life sciences : CMLS · 2021Review
- Review
- The solution structures of higher-order human telomere G-quadruplex multimers.Nucleic acids research · 2021Article
- The Cellular Functions and Molecular Mechanisms of G-Quadruplex Unwinding Helicases in Humans.Frontiers in molecular biosciences · 2021Review
- Article
- Role of POT1 in Human Cancer.Cancers · 2020Review
- Antisense Oligonucleotides Used to Identify Telomeric G-Quadruplexes in Metaphase Chromosomes and Fixed Cells by Fluorescence Lifetime Imaging Microscopy ofMolecules (Basel, Switzerland) · 2020Article
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7 authors at 1 institution in 1 country.
Funding
Abstract
The reaction mechanism by which the shelterin protein POT1 (Protection of Telomeres 1) unfolds human telomeric G-quadruplex structures is not fully understood. We report here kinetic, thermodynamic, hydrodynamic and computational studies that show that a conformational selection mechanism, in which POT1 binding is coupled to an obligatory unfolding reaction, is the most plausible mechanism. Stopped-flow kinetic and spectroscopic titration studies, along with isothermal calorimetry, were used to show that binding of the single-strand oligonucleotide d[TTAGGGTTAG] to POT1 is both fast (80 ms) and strong (-10.1 ± 0.3 kcal mol-1). In sharp contrast, kinetic studies showed the binding of POT1 to an initially folded 24 nt G-quadruplex structure is four orders of magnitude slower. Fluorescence, circular dichroism and analytical ultracentrifugation studies showed that POT1 binding is coupled to quadruplex unfolding, with a final complex with a stoichiometry of 2 POT1 per 24 nt DNA. The binding isotherm for the POT1-quadruplex interaction was sigmoidal, indicative of a complex reaction. A conformational selection model that includes equilibrium constants for both G-quadruplex unfolding and POT1 binding to the resultant single-strand provided an excellent quantitative fit to the experimental binding data. POT1 unfolded and bound to any conformational form of human telomeric G-quadruplex (antiparallel, hybrid, parallel monomers or a 48 nt sequence with two contiguous quadruplexes), but did not avidly interact with duplex DNA or with other G-quadruplex structures. Finally, molecular dynamics simulations provided a detailed structural model of a 2:1 POT1:DNA complex that is fully consistent with experimental biophysical results.
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