ArticleProceedings of the National Academy of Sciences of the United States of America2020
Target search and recognition mechanisms of glycosylase AlkD revealed by scanning FRET-FCS and Markov state models.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 19 papers.
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Who cites it
19 citing papers in PubMed.
- A 5-hydroxymethylcytosine DNA glycosylase provides defense against T-even bacteriophages.bioRxiv : the preprint server for biology · 2026Article
- A DNA Tetrahedron Delivery Asiatic Acid to Reprogram Mitochondrial Metabolism for Promoting Bone Regeneration via STAT3 Phosphorylation.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- FRET-FCS: Advancing comprehensive insights into complex biological systems.Biophysical journal · 2025Review
- Unlocking the chemistry facilitated by enzymes that process nucleic acids using quantum mechanical and combined quantum mechanics-molecular mechanics techniques.Pure and applied chemistry. Chimie pure et appliquee · 2025Review
- AlkD's Conformational Dynamics Regulated by Protein-DNA Interactions for Effective Target Recognition.The journal of physical chemistry letters · 2025Article
- Exploring transition states of protein conformational changes via out-of-distribution detection in the hyperspherical latent space.Nature communications · 2025Article
- Supervised multi-frame dual-channel denoising enables long-term single-molecule FRET under extremely low photon budget.Nature communications · 2025Article
- Single-molecule dynamic structural biology with vertically arranged DNA on a fluorescence microscope.Nature methods · 2025Article
- Transient interactions modulate the affinity of NF-κB transcription factors for DNA.Proceedings of the National Academy of Sciences of the United States of America · 2024Article
- Tutorial on how to build non-Markovian dynamic models from molecular dynamics simulations for studying protein conformational changes.The Journal of chemical physics · 2024Article
- Deubiquitination Detection of p53 Protein in Living Cells by Fluorescence Cross-Correlation Spectroscopy.ACS omega · 2023Article
- Review of FRET biosensing and its application in biomolecular detection.American journal of translational research · 2023Review
- Observing Protein One-Dimensional Sliding: Methodology and Biological Significance.Biomolecules · 2021Review
- Nonspecific interactions between SpCas9 and dsDNA sites located downstream of the PAM mediate facilitated diffusion to accelerate target search.Chemical science · 2021Article
- Markov State Models to Study the Functional Dynamics of Proteins in the Wake of Machine Learning.JACS Au · 2021Review
- Non-flipping DNA glycosylase AlkD scans DNA without formation of a stable interrogation complex.Communications biology · 2021Article
- Revealing atomic-scale molecular diffusion of a plant-transcription factor WRKY domain protein along DNA.Proceedings of the National Academy of Sciences of the United States of America · 2021Article
- Atomic resolution of short-range sliding dynamics of thymine DNA glycosylase along DNA minor-groove for lesion recognition.Nucleic acids research · 2021Article
- Searching for DNA Damage: Insights From Single Molecule Analysis.Frontiers in molecular biosciences · 2021Review
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Authors and funding
7 authors.
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No grant is acknowledged in the PubMed record.
Abstract
DNA glycosylase is responsible for repairing DNA damage to maintain the genome stability and integrity. However, how glycosylase can efficiently and accurately recognize DNA lesions across the enormous DNA genome remains elusive. It has been hypothesized that glycosylase translocates along the DNA by alternating between a fast but low-accuracy diffusion mode and a slow but high-accuracy mode when searching for DNA lesions. However, the slow mode has not been successfully characterized due to the limitation in the spatial and temporal resolutions of current experimental techniques. Using a newly developed scanning fluorescence resonance energy transfer (FRET)-fluorescence correlation spectroscopy (FCS) platform, we were able to observe both slow and fast modes of glycosylase AlkD translocating on double-stranded DNA (dsDNA), reaching the temporal resolution of microsecond and spatial resolution of subnanometer. The underlying molecular mechanism of the slow mode was further elucidated by Markov state model built from extensive all-atom molecular dynamics simulations. We found that in the slow mode, AlkD follows an asymmetric diffusion pathway, i.e., rotation followed by translation. Furthermore, the essential role of Y27 in AlkD diffusion dynamics was identified both experimentally and computationally. Our results provided mechanistic insights on how conformational dynamics of AlkD-dsDNA complex coordinate different diffusion modes to accomplish the search for DNA lesions with high efficiency and accuracy. We anticipate that the mechanism adopted by AlkD to search for DNA lesions could be a general one utilized by other glycosylases and DNA binding proteins.
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