ArticleeLife2023
Activity-based CRISPR scanning uncovers allostery in DNA methylation maintenance machinery.
Article in eLife, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 14 papers.
What it found
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Who cites it
14 citing papers in PubMed, 14 citations in OpenAlex.
- Live-cell DNMT3A "catalysome" mapping using engineered methyl-transfer pathways.Nucleic acids research · 2026Article
- Advancing risk gene discovery across the allele frequency spectrum.HGG advances · 2026Review
- Article
- Identification and understanding of allostery hotspots in proteins: Integration of deep mutational scanning and multi-faceted computational analyses.Journal of molecular biology · 2025Review
- Discovery of chromatin-based determinants of azacytidine and decitabine anti-cancer activity.bioRxiv : the preprint server for biology · 2025Article
- Selective chemical tracking of DNA methylomes in live cells.Epigenomics · 2025Article
- Article
- Exploring Binding Sites in Chagas Disease Protein TcP21 Using Integrated Mixed Solvent Molecular Dynamics Approaches.Journal of chemical information and modeling · 2025Article
- Non-canonical functions of UHRF1 maintain DNA methylation homeostasis in cancer cells.Nature communications · 2024Article
- Modulation of Allostery with Multiple Mechanisms by Hotspot Mutations in TetR.Journal of the American Chemical Society · 2024Article
- Modulation of Allostery with Multiple Mechanisms by Hotspot Mutations in TetR.bioRxiv : the preprint server for biology · 2023Article
- Article
- Base editor screens for in situ mutational scanning at scale.Molecular cell · 2023Review
- CRISPR-Suppressor Scanning for Systematic Discovery of Drug-Resistance Mutations.Current protocols · 2022Article
Corrections and comments
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Authors and funding
9 authors at 2 institutions in 1 country.
Funding
Abstract
Allostery enables dynamic control of protein function. A paradigmatic example is the tightly orchestrated process of DNA methylation maintenance. Despite the fundamental importance of allosteric sites, their identification remains highly challenging. Here, we perform CRISPR scanning on the essential maintenance methylation machinery-DNMT1 and its partner UHRF1-with the activity-based inhibitor decitabine to uncover allosteric mechanisms regulating DNMT1. In contrast to non-covalent DNMT1 inhibition, activity-based selection implicates numerous regions outside the catalytic domain in DNMT1 function. Through computational analyses, we identify putative mutational hotspots in DNMT1 distal from the active site that encompass mutations spanning a multi-domain autoinhibitory interface and the uncharacterized BAH2 domain. We biochemically characterize these mutations as gain-of-function, exhibiting increased DNMT1 activity. Extrapolating our analysis to UHRF1, we discern putative gain-of-function mutations in multiple domains, including key residues across the autoinhibitory TTD-PBR interface. Collectively, our study highlights the utility of activity-based CRISPR scanning for nominating candidate allosteric sites, and more broadly, introduces new analytical tools that further refine the CRISPR scanning framework.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.