ReviewFunctional & integrative genomics2025
Disrupting the epigenetic alliance: structural insights and therapeutic strategies targeting DNMT1-UHRF1.
Review in Functional & integrative genomics, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 1 paper.
What it found
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
1 citing paper in PubMed.
- DNA Methylation as a Programmable Information Layer: From Molecular Marks to Disease State Engineering.International journal of molecular sciences · 2026Review
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
7 authors.
Funding
Abstract
Maintenance DNA methylation relies on a coordinated partnership between DNMT1 and its chromatin cofactor UHRF1. UHRF1's SRA domain flips 5-methylcytosine out of hemimethylated DNA, and UHRF1-installed ubiquitin marks on histone H3 (H3K18/K23Ub; H3Ub₂) and PAF15 (PAF15Ub₂) are recognized by the DNMT1 RFTS domain to relieve autoinhibition and license copying of parental methylation during S phase. Tumors often upregulate this axis to enforce promoter hypermethylation programs, whereas approved azanucleosides act via DNMT1 trapping and are associated with DNA-damage-linked toxicities. Over ~ 15 years of structural work-from the 2008 SRA-DNA complexes to a 2022 cryo-EM structure of DNMT1 engaged with hemimethylated DNA and H3Ub₂-has mapped two tractable sites: the UHRF1-SRA aromatic cage and the ubiquitin-binding surface on DNMT1's RFTS. These insights catalyzed small-molecule discovery. The anthraquinone UM63 validated SRA-pocket engagement but intercalates into DNA; newer non-intercalating SRA-directed inhibitors AMSA-2 (hydroxyanthracene/anthrarobin) and MPB-7 (imidazoquinoline) retain low-micromolar potency. In cells, AMSA-2 and MPB-7 disrupt UHRF1/DNMT1 colocalization at replication foci and induce replication-coupled global hypomethylation, with preferential cytotoxicity in UHRF1-high cancer lines relative to non-transformed cells. Beyond SRA antagonism, DNMT1 can be down-regulated pharmacologically: the non-nucleoside inhibitor GSK-3,484,862 triggers proteasome-dependent DNMT1 degradation alongside hypomethylation, and the first DNMT1-targeting PROTAC (KW0113) achieves selective DNMT1 degradation and growth inhibition in AML models. Remaining hurdles include potency ceilings, nuclear exposure/pharmacokinetics, and adaptive chromatin rewiring upon DNMT1 inhibition; nonetheless, structure-guided optimization and degrader strategies outline a credible path to precision epigenetic therapeutics that directly disrupt the DNMT1-UHRF1 maintenance machinery.
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Identifiers
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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.