Affinage

DNMT1

DNA (cytosine-5)-methyltransferase 1 · UniProt P26358

Length
1616 aa
Mass
183.2 kDa
Annotated
2026-06-09
100 papers in source corpus 27 papers cited in narrative 27 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 9/9 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

DNMT1 is the principal maintenance DNA methyltransferase that propagates CpG methylation patterns across cell division, coupling its catalytic action to replication and chromatin state to preserve heterochromatin organization and genome stability (PMID:38376465, PMID:32675241). Its catalysis proceeds by nucleophilic attack of Cys1226 on cytosine C6 followed by rate-limiting methyl transfer from SAM to C5 (PMID:26929335). Recruitment and allosteric activation are governed by a UHRF1-dependent reader system: UHRF1 ubiquitinates histone H3 (including H3K18), DNMT1's ubiquitin-interacting motif and RFTS domain read H3K9me3/H3Ub, and its BAH1 domain reads H4K20me3, directing the enzyme to heterochromatin and retrotransposons such as LINE-1 (PMID:26065575, PMID:32675241, PMID:33941775). Cryo-EM resolved the activation switch, in which an RFTS–CXXC linker helix engages a 'Toggle' pocket to displace inhibitory domains and license the active DNA recognition conformation (PMID:36414620). Beyond classical maintenance, DNMT1 carries out de novo methylation at retrotransposons in a UHRF1-dependent manner, and on chromatin its activity requires linker DNA and cooperating remodeling enzymes (PMID:34140676, PMID:26496704). DNMT1 also coordinates repressive histone marks by directly binding and loading G9a onto chromatin and by interacting with HP1, linking H3K9 methylation to DNA methylation during gene silencing (PMID:17085482, PMID:17470536). Its abundance and activity are tuned by multiple post-translational controls: SIRT1 deacetylation of catalytic-domain lysines enhances activity (PMID:21947282), LSD1/L3MBTL3/CRL4-DCAF5-mediated methylation-dependent proteolysis at K142 controls turnover (PMID:29691401), and O-GlcNAcylation at S878 inhibits activity in response to high glucose (PMID:37470704). RNA structures including pUG-fold RNAs and locus-derived transcripts inhibit DNMT1 by blocking hemimethylated DNA binding, providing site-specific protection from methylation (PMID:24107992, PMID:36574982). A distinct DNMT1 isoform localizes to mitochondria and methylates the mitochondrial genome (PMID:28484249).

Mechanistic history

Synthesis pass · year-by-year structured walk · 25 steps
  1. 2002 Medium

    Established whether DNMT1 and the de novo enzyme DNMT3A act independently or cooperatively, showing directional stimulation of DNMT1 by prior DNMT3A methylation.

    Evidence In vitro methylation assays with purified enzymes in sequential incubations

    PMID:12383256

    Open questions at the time
    • Single lab, single method
    • No physical interaction tested in cells
    • Directionality shown in vitro only
  2. 2006 High

    Showed how DNA methylation is mechanistically coupled to repressive histone modification by identifying DNMT1 as the chromatin loading factor for G9a during replication.

    Evidence Reciprocal Co-IP, siRNA knockdown, replication-foci colocalization, and in vitro chromatin methylation

    PMID:17085482

    Open questions at the time
    • Structural basis of DNMT1-G9a binding not defined
    • Does not establish in vivo methylation consequence at endogenous loci
  3. 2007 High

    Defined HP1 as the functional bridge connecting G9a-generated H3K9 methylation to DNMT1-mediated DNA methylation during silencing.

    Evidence In vitro binding, Co-IP, chromatin methylation, and reporter assays in DNMT1-null vs wild-type cells

    PMID:17470536

    Open questions at the time
    • Endogenous target loci dependent on this bridge not mapped
    • HP1 isoform specificity not resolved
  4. 2011 High

    Resolved how PTMs tune DNMT1, showing SIRT1 deacetylation differentially controls catalytic activity versus methyltransferase-independent repression.

    Evidence Mass spectrometry of acetyl sites, in vitro deacetylation, mutagenesis, activity and cell cycle assays

    PMID:21947282

    Open questions at the time
    • Acetyltransferase responsible not identified
    • In vivo physiological context of each site not dissected
  5. 2011 Medium

    Identified upstream transcriptional control of DNMT1 by an ERRγ/SHP regulatory axis acting on the DNMT1 promoter.

    Evidence Reporter assays, ChIP, EMSA, and promoter mutagenesis

    PMID:21459093

    Open questions at the time
    • Physiological signal regulating this axis unclear
    • Single lab
  6. 2013 High

    Revealed RNA as a site-specific regulator of methylation, with locus-derived transcripts binding DNMT1 to protect their own genes from methylation.

    Evidence RNA immunoprecipitation of DNMT1-associated transcripts, deep sequencing, and genome-scale methylation profiling

    PMID:24107992

    Open questions at the time
    • Structural mode of RNA recognition not defined
    • Generality across the genome incomplete
  7. 2015 High

    Defined the histone-ubiquitin reading mechanism: DNMT1 UIM reads UHRF1-deposited H3 ubiquitin (H3K18), linking UHRF1 RING activity to DNMT1-mediated methylation.

    Evidence Systematic mutagenesis, complementation in UHRF1-deficient cells, and mass spectrometry of ubiquitination sites

    PMID:26065575

    Open questions at the time
    • Relative contribution of H3K18 vs other ubiquitin sites unresolved at this stage
  8. 2015 High

    Provided a structural basis for DNMT1 stabilization by USP7 via KG-linker lysines and acetylation-sensitive interaction.

    Evidence 2.9 Å crystal structure, mutagenesis, Co-IP, and protein stability assays

    PMID:25960197

    Open questions at the time
    • In vivo importance of USP7 for DNMT1 stability later challenged (#26)
  9. 2015 Medium

    Established the chromatin substrate constraints of DNMT1, showing it requires linker DNA and remodeling activity to methylate nucleosomal templates.

    Evidence In vitro nucleosome binding, footprinting, methylation assays, and remodeler co-incubation

    PMID:26496704

    Open questions at the time
    • Specific in vivo remodelers not definitively assigned
    • Single lab
  10. 2016 High

    Determined the catalytic transition state of human DNMT1, establishing methyl transfer as rate-limiting following Cys1226 attack on C6.

    Evidence Kinetic isotope effect measurements and quantum mechanical transition-state calculations

    PMID:26929335

    Open questions at the time
    • Does not address allosteric regulation of catalysis
  11. 2017 Medium

    Distinguished isoform-specific functions, showing a DNMT1 isoform localizes to and methylates the mitochondrial genome under stress.

    Evidence Subcellular fractionation, ectopic expression imaging, and mitochondrial bisulfite sequencing

    PMID:28484249

    Open questions at the time
    • Endogenous isoform3 mitochondrial targeting not validated
    • Functional consequence of mtDNA methylation limited
  12. 2018 High

    Defined the writer/reader/eraser cycle controlling DNMT1 turnover through K142 methylation-dependent proteolysis.

    Evidence Co-IP, ubiquitination assays, L3MBTL3 mouse knockout, and genome-wide methylation analysis

    PMID:29691401

    Open questions at the time
    • Methyltransferase writing K142 not identified here
    • Cell-cycle timing details partial
  13. 2018 Medium

    Challenged the USP7/GK-repeat stabilization model, arguing DNMT1 homeostasis is controlled mainly transcriptionally.

    Evidence Western blotting in USP7-deficient cells, GK-to-GQ mutagenesis, and methylation rescue in Dnmt1-null ES cells

    PMID:29482658

    Open questions at the time
    • Directly contradicts #25960197 on USP7 role
    • Negative-result interpretation cell-context dependent
  14. 2018 Medium

    Connected focal adhesion signaling to epigenetic silencing via Kindlin-2 stabilization of DNMT1 at the E-cadherin promoter.

    Evidence Co-IP, protein stability assay, ChIP, methylation-specific PCR, and transgenic mouse model

    PMID:30287284

    Open questions at the time
    • Mechanism of stabilization unclear
    • Single lab
  15. 2018 Medium

    Demonstrated the developmental requirement for UHRF1/DNMT1 maintenance methylation in tissue-specific proliferation and survival.

    Evidence Zebrafish uhrf1 and dnmt1 mutants with lens transplantation and histology

    PMID:21126517

    Open questions at the time
    • Cell-autonomy not fully resolved
    • Direct methylation targets driving phenotype unmapped
  16. 2019 Medium

    Identified a methylation homeostasis circuit in which SET8 methylation of UHRF1 limits its abundance and thereby DNMT1 stability across the cell cycle.

    Evidence In vitro methylation, ubiquitination, stability assays, and genome-wide methylation profiling

    PMID:31400111

    Open questions at the time
    • Single lab
    • Quantitative contribution to global methylation balance unclear
  17. 2019 High

    Established Stella as a guardian against aberrant DNMT1/UHRF1-driven de novo methylation in oocytes through control of UHRF1 nuclear localization.

    Evidence Stella knockout mice with UHRF1/DNMT1 epistasis double knockouts, bisulfite sequencing, and localization imaging

    PMID:30487604

    Open questions at the time
    • Mechanism by which Stella restricts UHRF1 nuclear entry partly defined
    • Generality beyond oocytes untested
  18. 2020 High

    Characterized the RFTS domain as a non-canonical reader of combined H3K9me3/H3Ub required for DNMT1 localization and global methylation.

    Evidence Structural and biochemical binding assays, mutagenesis, stem-cell localization, and genome-wide methylation

    PMID:32675241

    Open questions at the time
    • Quantitative interplay with other reader domains addressed later (#9)
  19. 2021 High

    Defined the BAH1 domain as an H4K20me3 reader enabling heterochromatin and LINE-1 targeting, completing a multivalent allosteric activation logic with RFTS.

    Evidence Structural/biochemical characterization, BAH1 mutagenesis, genome-wide bisulfite sequencing, and radiation-sensitivity assays

    PMID:33941775

    Open questions at the time
    • Stoichiometry of simultaneous multivalent engagement unresolved
  20. 2021 High

    Revised the maintenance-only view by showing DNMT1 performs UHRF1-dependent de novo methylation at retrotransposons overlapping Trim28/H3K9me3 regions.

    Evidence Whole-genome and Nanopore sequencing in methylation-depleted mouse ESCs, knockout lines, and in vitro methylation

    PMID:34140676

    Open questions at the time
    • Extent of de novo activity in normal (non-depleted) cells unclear
  21. 2022 High

    Visualized the activation switch, showing an RFTS-CXXC linker helix engages a Toggle pocket to displace inhibitory domains and license the active conformation.

    Evidence Cryo-EM of human DNMT1 bound to hemimethylated DNA and ubiquitinated H3 with functional validation

    PMID:36414620

    Open questions at the time
    • Dynamics of the conformational transition in solution not directly captured
  22. 2023 Medium

    Identified RNA structure–specific inhibition, with pUG-fold RNAs blocking hemimethylated DNA binding and DNMT1 binding its own mRNA.

    Evidence RNA-protein binding, in vitro methylation inhibition, and competition assays

    PMID:36574982

    Open questions at the time
    • In vivo relevance of pUG-fold inhibition untested
    • Single lab
  23. 2023 High

    Linked glucose metabolism to the epigenome via O-GlcNAcylation of DNMT1 at S878 that inhibits activity and causes PMD demethylation.

    Evidence Mass spectrometry, alanine mutagenesis, activity assays, bisulfite sequencing, and DNA-damage assays

    PMID:37470704

    Open questions at the time
    • OGT recruitment mechanism not defined
    • Causal chain to apoptosis partially correlative
  24. 2023 Medium

    Showed a DNMT1-selective non-nucleoside inhibitor acts by UHRF1-dependent proteasomal degradation rather than catalytic blockade alone.

    Evidence Western blotting, proteasome and mRNA controls, Uhrf1 knockout epistasis in mESCs, and genome-wide methylation

    PMID:37206360

    Open questions at the time
    • Molecular trigger linking inhibitor binding to degradation unclear
    • Single lab
  25. 2024 High

    Demonstrated the systems-level consequence of DNMT1 loss: progressive passive demethylation reorganizes heterochromatin, chromosomal compartments, and nuclear-peripheral positioning with G1 arrest.

    Evidence Inducible DNMT1 degradation, whole-genome bisulfite sequencing, Hi-C, lamin-association sequencing, and cell-cycle analysis

    PMID:38376465

    Open questions at the time
    • Causal order of methylation loss vs 3D genome change not fully separated
    • DNMT3B's collaborative contribution quantitatively undefined

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the multiple competing regulatory inputs—reader-domain allostery, RNA inhibition, metabolic PTMs, and ubiquitin/methylation-dependent turnover—are integrated in space and time to set locus-specific methylation in normal versus diseased cells remains unresolved.
  • No unified quantitative model of competing inputs
  • Disease-causative DNMT1 mutations not represented in this corpus
  • Endogenous balance between maintenance and de novo activity unquantified

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140097 catalytic activity, acting on DNA 4 GO:0042393 histone binding 3 GO:0140110 transcription regulator activity 3 GO:0003677 DNA binding 2 GO:0003723 RNA binding 2 GO:0016740 transferase activity 2
Localization
GO:0000228 nuclear chromosome 3 GO:0005634 nucleus 2 GO:0005739 mitochondrion 1
Pathway
R-HSA-4839726 Chromatin organization 5 R-HSA-1640170 Cell Cycle 3 R-HSA-74160 Gene expression (Transcription) 3 R-HSA-69306 DNA Replication 2
Partners
DMAP1G9AHP1L3MBTL3PCNASIRT1UHRF1USP7

Evidence

Reading pass · 27 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2006 DNMT1 directly binds the histone methyltransferase G9a both in vivo and in vitro, co-localizes with G9a and H3K9me2 at replication foci, and forms a ternary complex with PCNA on chromatin during replication. DNMT1 acts as the primary loading factor for G9a onto chromatin; siRNA knockdown of DNMT1 impairs G9a loading and H3K9 methylation. The DNMT1–G9a complex enhances both DNA and histone methylation on in vitro assembled chromatin substrates, coordinating DNA and H3K9 methylation during cell division. Co-immunoprecipitation (in vivo and in vitro), siRNA knockdown, immunofluorescence co-localization at replication foci, in vitro chromatin methylation assay Genes & development High 17085482
2007 HP1 family members (HP1α, HP1β, HP1γ) physically interact with DNMT1 in vitro and in vivo. G9a-mediated H3K9 methylation creates a binding platform for HP1, and HP1–DNMT1 interaction results in increased DNA methylation on DNA and chromatin templates in vitro. Binding of GAL4-HP1 to a reporter is sufficient to induce repression and DNA methylation in DNMT1 wild-type but not DNMT1-null cells, placing HP1 as a functional bridge between G9a-mediated histone methylation and DNMT1-mediated DNA methylation during gene silencing. In vitro binding assay, Co-immunoprecipitation, in vitro DNA methylation on chromatin templates, reporter assay in DNMT1-null vs. wild-type cells, ChIP Genes & development High 17470536
2011 SIRT1 physically associates with DNMT1 and deacetylates it in vitro and in vivo. Mass spectrometry identified 12 acetylated lysine sites on DNMT1. Deacetylation of Lys1349 and Lys1415 in the catalytic domain enhances DNMT1 methyltransferase activity, while deacetylation of lysines in the GK linker decreases DNMT1's methyltransferase-independent transcriptional repression. Deacetylation of all identified sites abrogates DNMT1 binding to SIRT1 and impairs DNMT1's ability to regulate G2/M cell cycle transition. Mass spectrometry, in vitro deacetylation assay, Co-immunoprecipitation, site-directed mutagenesis, methyltransferase activity assay, cell cycle analysis Molecular and cellular biology High 21947282
2013 Active transcription at the CEBPA locus produces an RNA that binds DNMT1 and prevents methylation of the CEBPA gene locus. Deep sequencing of DNMT1-associated transcripts combined with genome-scale methylation profiling extended this finding to numerous gene loci, establishing that RNA–DNMT1 interactions regulate site-specific DNA methylation. RNA immunoprecipitation of DNMT1-associated RNAs, deep sequencing, genome-scale methylation profiling, functional RNA-knockdown experiments Nature High 24107992
2015 DNMT1 contains a ubiquitin interacting motif (UIM) in its N-terminal regulatory domain that binds ubiquitinated histone H3 tails; this interaction is essential for DNA methylation in vivo. UHRF1's RING domain ubiquitin ligase activity ubiquitinates H3K18 (a novel target identified by mass spectrometry), and UHRF1 PHD binding to unmodified H3R2 is required for H3 ubiquitination and subsequent DNMT1-mediated DNA methylation. UHRF1 SRA domain recognizes hemimethylated DNA and TTD reads H3K9me3. Systematic mutagenesis, complementation assays in UHRF1-deficient cells, mass spectrometry, bioinformatics identification of UIM, functional DNA methylation assays Cell research High 26065575
2015 Crystal structure of DNMT1 in complex with USP7 at 2.9 Å resolution revealed that interaction is mediated by an acidic pocket in USP7 and lysine residues in DNMT1's KG linker. This interaction is required for USP7-mediated stabilization of DNMT1. Acetylation of KG linker lysines impairs the DNMT1–USP7 interaction and promotes DNMT1 degradation. HDAC inhibitor treatment increases acetylated DNMT1 and decreases total DNMT1 protein. Crystal structure (2.9 Å), mutagenesis, co-immunoprecipitation, protein stability assays, HDAC inhibitor treatment Nature communications High 25960197
2016 Kinetic isotope effect experiments guided quantum mechanical calculations to determine the transition state structure of human DNMT1. Methyl transfer from SAM to cytosine C5 occurs after nucleophilic attack of Cys1226 on cytosine C6, and methyl transfer is the chemically rate-limiting step. Electrostatic potential maps identified the electronic basis for protein–reactant interactions at the transition state. Kinetic isotope effect measurements, quantum mechanical transition state calculations Proceedings of the National Academy of Sciences of the United States of America High 26929335
2018 Methylation of DNMT1 at lysine 142 targets it for proteolysis: L3MBTL3 binds K142-methylated DNMT1 and recruits CRL4DCAF5 ubiquitin ligase to degrade DNMT1. LSD1 demethylates DNMT1 K142 and PHF20L1 act primarily in S phase to prevent this degradation. Mouse L3MBTL3 deletion causes DNMT1 protein accumulation, increased genomic DNA methylation, and late embryonic lethality. Co-immunoprecipitation, ubiquitination assays, genetic mouse knockout (L3MBTL3-/-), western blotting, genome-wide DNA methylation analysis Nature communications High 29691401
2020 The RFTS domain of DNMT1 acts as a specific reader for H3K9me3/H3Ub via a recognition mode distinct from typical trimethyl-lysine readers, as established by structural and biochemical characterization. Disruption of RFTS–H3K9me3Ub interaction impairs DNMT1 localization in stem cells and profoundly reduces global DNA methylation and genomic stability. Structural determination, biochemical binding assays, mutagenesis, cellular localization studies in stem cells, genome-wide DNA methylation analysis Proceedings of the National Academy of Sciences of the United States of America High 32675241
2021 DNMT1's first bromo-adjacent-homology domain (BAH1) specifically recognizes H4K20me3, and this engagement ensures heterochromatin targeting of DNMT1 and DNA methylation at LINE-1 retrotransposons. Interplay between the RFTS and BAH1 domains allosterically regulates DNMT1 activity, and multivalent readout of H3K9me3/H3Ub (RFTS) and H4K20me3 (BAH1) together controls global and focal DNA methylation and genomic resistance to radiation-induced damage. Structural and biochemical characterization, mutagenesis of DNMT1 BAH1 domain, genome-wide bisulfite sequencing, radiation sensitivity assays Nature communications High 33941775
2021 Dnmt1 displays de novo methylation activity in vitro and in vivo, with specific targeting to retrotransposons. In methylation-depleted mouse ESCs, this de novo activity depends on Uhrf1 and genomic recruitment overlaps with Uhrf1, Trim28, and H3K9me3-enriched regions. Dnmt1 can thus catalyze DNA methylation in both a de novo and maintenance context, especially at retrotransposons. Whole-genome bisulfite sequencing, long-read Nanopore sequencing, genetically engineered methylation-depleted mouse ESCs, knockout lines, in vitro methylation assays Nature structural & molecular biology High 34140676
2022 Cryo-EM structure of human DNMT1 bound to hemimethylated DNA and ubiquitinated histone H3 revealed that a previously unstudied linker between the RFTS and CXXC domains contains a conserved α-helix that engages a 'Toggle' pocket, displacing an inhibitory linker and allowing the DNA Recognition Helix to adopt the active conformation. This is accompanied by large-scale reorganization of the inhibitory RFTS and CXXC domains, providing a mechanistic basis for DNMT1 activation by its two natural activators. Cryo-EM structure determination with functional validation Nature communications High 36414620
2002 Dnmt3a and Dnmt1 functionally cooperate in de novo methylation: prior methylation by Dnmt3a stimulates Dnmt1 activity ~5-fold on the same substrate, because pre-existing methyl groups activate Dnmt1 for methylation of unmodified DNA. No physical interaction between the two enzymes is required for this stimulation; Dnmt1 preceding Dnmt3a did not produce stimulation, establishing the directionality of cooperation. In vitro methylation assay with purified enzymes, sequential incubation experiments European journal of biochemistry Medium 12383256
2004 RGS6 interacts with DMAP1 (a component of the DNMT1 repressor complex) and co-immunoprecipitates DMAP1 and DNMT1 in a DMAP1-dependent manner. RGS6 inhibits the transcriptional repressor activity of DMAP1, establishing RGS6 as a regulator of the DNMT1 transcriptional repression complex. Yeast two-hybrid screen, co-immunoprecipitation, domain mapping, transcriptional repression assay The Journal of biological chemistry Medium 14734556
2004 Dnmt1-/- embryonic stem cells exhibit significantly elevated microsatellite instability at three of five markers compared to wild-type cells, indicating that Dnmt1 plays an integrating role in DNA replication and/or mismatch repair strand discrimination. PCR-based microsatellite instability assay in Dnmt1-null vs. wild-type mouse ES cells Oncogene Medium 15378011
2017 A specific isoform of DNMT1 (isoform3, not isoform1 as previously reported) localizes to mitochondria when ectopically expressed, methylates CpG regions of the mitochondrial genome, and affects mitochondrial biology and function. DNMT1-isoform1 localizes exclusively to the nucleus. Under oxidative and nutritional stress, isoform3 is downregulated, resulting in mitochondrial genome hypomethylation. Subcellular fractionation, ectopic expression with localization imaging, mitochondrial genome bisulfite sequencing, stress-condition experiments Scientific reports Medium 28484249
2019 SET8 methyltransferase methylates UHRF1 at lysine 385, triggering its ubiquitination and degradation, which consequently reduces DNMT1 stability and prevents excessive DNA methylation. Conversely, LSD1 demethylates UHRF1 (and DNMT1) to stabilize both proteins. SET8-mediated UHRF1 downregulation in G2/M suppresses DNMT1-mediated methylation on post-replicated DNA, establishing a methylation homeostasis mechanism. In vitro methylation assay, ubiquitination assay, protein stability assays, cell-cycle analysis, genome-wide DNA methylation Nucleic acids research Medium 31400111
2019 Stella (encoded by Dppa3) prevents aberrant de novo DNA methylation in oocytes mediated by DNMT1 and UHRF1. Loss of Stella leads to ectopic nuclear accumulation of UHRF1, which causes mislocalization of DNMT1 to the nucleus, resulting in genome-wide hypermethylation. Genetic analysis (knockout of UHRF1 and DNMT1 in Stella-deficient oocytes) confirmed that UHRF1 and DNMT1 are the primary drivers of aberrant methylation. Genetic mouse knockouts (Stella-/-, epistasis with UHRF1 and DNMT1 knockout), genome-wide bisulfite sequencing, subcellular localization imaging Nature High 30487604
2015 Dnmt1 requires linker DNA to bind nucleosomes, binds cooperatively to DNA with a minimum length requirement of ~20 bp, and preferentially methylates DNA linker regions on nucleosomes. Dnmt1 cannot methylate nucleosomal CpG sites on mononucleosomes or nucleosomal arrays unless chromatin remodeling enzymes create a dynamic chromatin state; Dnmt1 functionally interacts with specific chromatin remodeling enzymes to enable complete methylation of hemimethylated DNA in chromatin. In vitro nucleosome binding assays, DNA footprinting, in vitro methylation assays on nucleosomes and nucleosomal arrays, chromatin remodeling co-incubation experiments PloS one Medium 26496704
2023 GSK-3484862, a non-nucleoside DNMT1-selective inhibitor, targets DNMT1 for proteasome-dependent protein degradation in cancer cell lines and mouse ESCs, causing global hypomethylation without loss of DNMT1 mRNA. In mouse ESCs, Dnmt1 degradation induced by GSK-3484862 requires Uhrf1 and its E3 ubiquitin ligase activity. DNMT1 depletion and hypomethylation are reversible after inhibitor removal. Western blotting, proteasome inhibitor rescue, mRNA analysis, genetic Uhrf1 knockout in mESCs, genome-wide methylation analysis NAR cancer Medium 37206360
2023 DNMT1 exhibits strong and specific affinity for GU-rich RNAs that form a pUG-fold (noncanonical G-quadruplex). pUG-fold-capable RNAs inhibit DNMT1 methyltransferase activity by blocking binding of hemimethylated DNA. DNMT1 also interacts with its own nuclear mRNA, suggesting multiple RNA binding modes. RNA–protein binding assays, in vitro methylation inhibition assays, RNA competition experiments RNA (New York, N.Y.) Medium 36574982
2023 DNMT1 is O-GlcNAcylated at serine 878 (identified by mass spectrometry and alanine mutagenesis), and elevated O-GlcNAcylation from high glucose inhibits DNMT1 methyltransferase activity, causing preferential loss of DNA methylation at partially methylated domains (PMDs). This loss of methylation corresponds with increased DNA damage and apoptosis, establishing O-GlcNAcylation as a mechanism linking glucose metabolism to epigenome regulation via DNMT1. Mass spectrometry, alanine mutagenesis, in vitro and cellular methyltransferase activity assays, genome-wide bisulfite sequencing, DNA damage assays eLife High 37470704
2018 Kindlin-2 physically interacts with DNMT1, increases DNMT1 protein stability, and increases DNMT1 occupancy at the E-cadherin promoter, thereby promoting CpG island methylation and suppression of E-cadherin expression. This mechanism links focal adhesion signaling to epigenetic gene silencing in breast cancer. Co-immunoprecipitation, DNMT1 protein stability assay, ChIP at E-cadherin promoter, methylation-specific PCR, transgenic mouse model The international journal of biochemistry & cell biology Medium 30287284
2011 ERRγ (estrogen-related receptor γ) functions as a transcriptional activator of DNMT1 expression by directly binding to response elements (ERE1/ERE2) in the DNMT1 promoter. The nuclear receptor SHP represses DNMT1 expression by inhibiting ERRγ transactivity, reducing ERRγ recruitment to the DNMT1 promoter, and shifting local chromatin from active to inactive conformation. Reporter assay, ChIP, electrophoretic mobility shift assay (EMSA), promoter mutagenesis FEBS letters Medium 21459093
2018 DNMT1 maintains DNA methylation in collaboration with UHRF1 at replication forks; in zebrafish, loss of either uhrf1 or catalytically active dnmt1 causes defects in lens epithelial cell proliferation and a wave of apoptosis, followed by secondary fiber cell degeneration. Lens transplant experiments established that these functions are required lens-autonomously but may not be strictly cell-autonomous. Zebrafish genetic mutants (uhrf1 and dnmt1), lens transplantation, histology, gene expression analysis Developmental biology Medium 21126517
2024 DNMT1 and DNMT3B, but not DNMT3A, cooperate to maintain DNA methylation: inducible DNMT1 depletion in human cells reveals that gradual passive demethylation through cell divisions leads to progressive and reversible changes in heterochromatin organization, chromosomal compartmentalization, and peripheral localization, accompanied by G1 arrest. Inducible DNMT1 degradation cell models, whole-genome bisulfite sequencing, Hi-C (compartmentalization), lamin association sequencing, cell cycle analysis The Journal of cell biology High 38376465
2018 Independent lines of evidence indicate that DNMT1 protein homeostasis in somatic cells is controlled primarily at the transcriptional level and that interaction of USP7 with the GK repeats of DNMT1 is unlikely to play a major role in DNMT1 stabilization: DNMT1 is present at normal levels in cells with undetectable USP7; substitution of GK repeats with GQ repeats (preventing lysine acetylation) does not affect DNMT1 stability or ability to restore genomic methylation in Dnmt1-null ES cells; and USP7 and PCNA are recruited to replication sites independently of DNMT1. Western blotting in USP7-deficient cells, GK-to-GQ substitution mutagenesis, methylation rescue assay in Dnmt1-null ES cells, replication focus imaging Epigenetics & chromatin Medium 29482658

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2006 Direct interaction between DNMT1 and G9a coordinates DNA and histone methylation during replication. Genes & development 419 17085482
2013 DNMT1-interacting RNAs block gene-specific DNA methylation. Nature 407 24107992
2018 A circular RNA circ-DNMT1 enhances breast cancer progression by activating autophagy. Oncogene 270 29973691
2007 Functional cooperation between HP1 and DNMT1 mediates gene silencing. Genes & development 260 17470536
2018 Stella safeguards the oocyte methylome by preventing de novo methylation mediated by DNMT1. Nature 226 30487604
2002 Dnmt3a and Dnmt1 functionally cooperate during de novo methylation of DNA. European journal of biochemistry 205 12383256
2015 DNMT1 is essential for mammary and cancer stem cell maintenance and tumorigenesis. Nature communications 199 25908435
2015 DNA methylation requires a DNMT1 ubiquitin interacting motif (UIM) and histone ubiquitination. Cell research 190 26065575
2011 SIRT1 deacetylates the DNA methyltransferase 1 (DNMT1) protein and alters its activities. Molecular and cellular biology 184 21947282
2020 DNMT1: A key drug target in triple-negative breast cancer. Seminars in cancer biology 157 32461152
2019 Inhibition of a G9a/DNMT network triggers immune-mediated bladder cancer regression. Nature medicine 157 31270502
2019 Intestinal PPARα Protects Against Colon Carcinogenesis via Regulation of Methyltransferases DNMT1 and PRMT6. Gastroenterology 145 31154022
2015 Molecular mechanism for USP7-mediated DNMT1 stabilization by acetylation. Nature communications 129 25960197
2021 DNMT1-mediated methylation of BEX1 regulates stemness and tumorigenicity in liver cancer. Journal of hepatology 123 34217777
2021 Inhibition of DNMT-1 alleviates ferroptosis through NCOA4 mediated ferritinophagy during diabetes myocardial ischemia/reperfusion injury. Cell death discovery 121 34588431
2017 DNA Methylation Targeting: The DNMT/HMT Crosstalk Challenge. Biomolecules 118 28067760
2021 Dnmt1 has de novo activity targeted to transposable elements. Nature structural & molecular biology 117 34140676
2018 Structural Basis of DNMT1 and DNMT3A-Mediated DNA Methylation. Genes 116 30544982
2006 Quantitative analysis of associations between DNA hypermethylation, hypomethylation, and DNMT RNA levels in ovarian tumors. Oncogene 110 16532039
2003 Mutation of the DNA methyltransferase (DNMT) 1 gene in human colorectal cancers. Cancer letters 104 12637155
2000 Transcriptional regulation of the human DNA Methyltransferase (dnmt1) gene. Gene 100 10721735
2019 Oncogenic Roles and Inhibitors of DNMT1, DNMT3A, and DNMT3B in Acute Myeloid Leukaemia. Biomarker insights 98 31105426
2011 Epigenetic regulation of DNA methyltransferases: DNMT1 and DNMT3B in gliomas. Journal of neuro-oncology 97 21229291
2012 DNMT (DNA methyltransferase) inhibitors radiosensitize human cancer cells by suppressing DNA repair activity. Radiation oncology (London, England) 93 22429326
2004 Dnmt1 expression in pre- and postimplantation embryogenesis and the maintenance of IAP silencing. Molecular and cellular biology 91 14749379
2021 DNMT1 reads heterochromatic H4K20me3 to reinforce LINE-1 DNA methylation. Nature communications 90 33941775
2019 Coordinated Dialogue between UHRF1 and DNMT1 to Ensure Faithful Inheritance of Methylated DNA Patterns. Genes 90 30669400
2020 Direct readout of heterochromatic H3K9me3 regulates DNMT1-mediated maintenance DNA methylation. Proceedings of the National Academy of Sciences of the United States of America 89 32675241
2014 Inhibition of HDAC1 and DNMT1 modulate RGS10 expression and decrease ovarian cancer chemoresistance. PloS one 79 24475290
2022 NOTCH-YAP1/TEAD-DNMT1 Axis Drives Hepatocyte Reprogramming Into Intrahepatic Cholangiocarcinoma. Gastroenterology 76 35550144
2011 Dnmt1 structure and function. Progress in molecular biology and translational science 74 21507353
2011 Expression of DNMT1 and DNMT3a are regulated by GLI1 in human pancreatic cancer. PloS one 73 22110720
2015 Local chromatin microenvironment determines DNMT activity: from DNA methyltransferase to DNA demethylase or DNA dehydroxymethylase. Epigenetics 72 26098813
2010 Uhrf1 and Dnmt1 are required for development and maintenance of the zebrafish lens. Developmental biology 72 21126517
2019 SET8 prevents excessive DNA methylation by methylation-mediated degradation of UHRF1 and DNMT1. Nucleic acids research 71 31400111
2017 DNA Methyltransferase1 (DNMT1) Isoform3 methylates mitochondrial genome and modulates its biology. Scientific reports 71 28484249
2023 DNMT and HDAC inhibition induces immunogenic neoantigens from human endogenous retroviral element-derived transcripts. Nature communications 70 37872136
2017 HDAC3 regulates DNMT1 expression in multiple myeloma: therapeutic implications. Leukemia 69 28490812
2022 Structural basis for activation of DNMT1. Nature communications 68 36414620
2016 Domain Structure of the Dnmt1, Dnmt3a, and Dnmt3b DNA Methyltransferases. Advances in experimental medicine and biology 68 27826835
2003 DNMT cooperativity--the developing links between methylation, chromatin structure and cancer. BioEssays : news and reviews in molecular, cellular and developmental biology 68 14579248
2020 TET repression and increased DNMT activity synergistically induce aberrant DNA methylation. The Journal of clinical investigation 62 32663196
2023 DNA damage, demethylation and anticancer activity of DNA methyltransferase (DNMT) inhibitors. Scientific reports 61 37045940
2018 Reactivation of endogenous retroviral elements via treatment with DNMT- and HDAC-inhibitors. Cell cycle (Georgetown, Tex.) 59 29633898
2014 Novel DNA methyltransferase-1 (DNMT1) depleting anticancer nucleosides, 4'-thio-2'-deoxycytidine and 5-aza-4'-thio-2'-deoxycytidine. Cancer chemotherapy and pharmacology 58 24908436
2015 Developmental exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin alters DNA methyltransferase (dnmt) expression in zebrafish (Danio rerio). Toxicology and applied pharmacology 57 25732252
2004 RGS6 interacts with DMAP1 and DNMT1 and inhibits DMAP1 transcriptional repressor activity. The Journal of biological chemistry 54 14734556
2024 Dual inhibitors of DNMT and HDAC induce viral mimicry to induce antitumour immunity in breast cancer. Cell death discovery 53 38490978
2017 DNMT1, DNMT3A and DNMT3B proteins are differently expressed in mouse oocytes and early embryos. Journal of molecular histology 53 29027601
2018 Methylated DNMT1 and E2F1 are targeted for proteolysis by L3MBTL3 and CRL4DCAF5 ubiquitin ligase. Nature communications 52 29691401
2018 DNMT and HDAC inhibitors together abrogate endotoxemia mediated macrophage death by STAT3-JMJD3 signaling. The international journal of biochemistry & cell biology 51 30010012
2022 DNMT and EZH2 inhibitors synergize to activate therapeutic targets in hepatocellular carcinoma. Cancer letters 49 36087682
2010 Pancreatic cancer DNMT1 expression and sensitivity to DNMT1 inhibitors. Cancer biology & therapy 49 20234167
2016 Human DNMT1 transition state structure. Proceedings of the National Academy of Sciences of the United States of America 48 26929335
2011 Hormonal therapy promotes hormone-resistant phenotype by increasing DNMT activity and expression in prostate cancer models. Endocrinology 48 21990314
2024 The Role of DNMT Methyltransferases and TET Dioxygenases in the Maintenance of the DNA Methylation Level. Biomolecules 46 39334883
2023 GSK-3484862 targets DNMT1 for degradation in cells. NAR cancer 46 37206360
2017 Hinokitiol induces DNA demethylation via DNMT1 and UHRF1 inhibition in colon cancer cells. BMC cell biology 46 28241740
2022 DNMT1: catalytic and non-catalytic roles in different biological processes. Epigenomics 44 35410490
2012 DNA methyltransferases1 (DNMT1) and 3a (DNMT3a) colocalize with GAD67-positive neurons in the GAD67-GFP mouse brain. The Journal of comparative neurology 40 22134929
2024 DNMT aberration-incurred GPX4 suppression prompts osteoblast ferroptosis and osteoporosis. Bone research 39 39617773
2007 Zinc-fingers and homeoboxes 1 (ZHX1) binds DNA methyltransferase (DNMT) 3B to enhance DNMT3B-mediated transcriptional repression. Biochemical and biophysical research communications 39 17303076
2020 Inhibition of DNMT1 and ERRα crosstalk suppresses breast cancer via derepression of IRF4. Oncogene 38 32855526
2003 Human DNA methyltransferase gene DNMT1 is regulated by the APC pathway. Carcinogenesis 38 12538344
2004 DNA methyltransferase Dnmt1 and mismatch repair. Oncogene 37 15378011
2023 Insights into DNMT1 and programmed cell death in diseases. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 33 37871559
2022 DNA methyltransferase 1 (DNMT1) suppresses mitophagy and aggravates heart failure via the microRNA-152-3p/ETS1/RhoH axis. Laboratory investigation; a journal of technical methods and pathology 33 35149775
2011 Nuclear receptor SHP inhibition of Dnmt1 expression via ERRγ. FEBS letters 32 21459093
2022 Domain Structure of the Dnmt1, Dnmt3a, and Dnmt3b DNA Methyltransferases. Advances in experimental medicine and biology 31 36350506
2021 TERT and DNMT1 expression predict sensitivity to decitabine in gliomas. Neuro-oncology 31 32882013
2022 DNMT1 facilitates growth of breast cancer by inducing MEG3 hyper-methylation. Cancer cell international 30 35109842
2024 Asperosaponin VI inhibition of DNMT alleviates GPX4 suppression-mediated osteoblast ferroptosis and diabetic osteoporosis. Journal of advanced research 29 39647633
2018 Kindlin-2 interacts with and stabilizes DNMT1 to promote breast cancer development. The international journal of biochemistry & cell biology 28 30287284
2011 Recruitment of Dnmt1 roles of the SRA protein Np95 (Uhrf1) and other factors. Progress in molecular biology and translational science 28 21507355
2015 Characterization of Dnmt1 Binding and DNA Methylation on Nucleosomes and Nucleosomal Arrays. PloS one 25 26496704
2023 DNMT1 mutant ants develop normally but have disrupted oogenesis. Nature communications 24 37072475
2021 DNMT1 Inhibitor Restores RUNX2 Expression and Mineralization in Periodontal Ligament Cells. DNA and cell biology 24 33751901
2024 Non-nucleoside inhibitors of DNMT1 and DNMT3 for targeted cancer therapy. Pharmacological research 23 39079576
2020 The Role of DNMT and HDACs in the Fetal Programming of Hypertension by Glucocorticoids. Oxidative medicine and cellular longevity 23 32318239
2023 Targeted systematic evolution of an RNA platform neutralizing DNMT1 function and controlling DNA methylation. Nature communications 22 36609400
2023 Triclocarban triggers osteoarthritis via DNMT1-mediated epigenetic modification and suppression of COL2A in cartilage tissues. Journal of hazardous materials 22 36680903
2022 DNMT1 inhibition by pUG-fold quadruplex RNA. RNA (New York, N.Y.) 21 36574982
2014 Cytostatic and apoptotic effects of DNMT and HDAC inhibitors in endometrial cancer cells. Current pharmaceutical design 21 23888960
2008 Silencing DNA methyltransferase (DNMT) enhances glioma chemosensitivity. Oligonucleotides 21 18928331
2020 DNA Methyltransferase 1 (DNMT1) Acts on Neurodegeneration by Modulating Proteostasis-Relevant Intracellular Processes. International journal of molecular sciences 20 32751461
2020 DNMT1 Promotes Genome Methylation and Early Embryo Development in Cockroaches. iScience 20 33294787
2019 Dynamics of DNA Methylation and DNMT Expression During Gametogenesis and Early Development of Scallop Patinopecten yessoensis. Marine biotechnology (New York, N.Y.) 20 30680591
2019 DNMT and HDAC inhibitors modulate MMP-9-dependent H3 N-terminal tail proteolysis and osteoclastogenesis. Epigenetics & chromatin 20 30992059
2019 ZNF479 downregulates metallothionein-1 expression by regulating ASH2L and DNMT1 in hepatocellular carcinoma. Cell death & disease 20 31138789
2018 Independent functions of DNMT1 and USP7 at replication foci. Epigenetics & chromatin 20 29482658
2017 DNMT1 regulates human endometrial carcinoma cell proliferation. OncoTargets and therapy 20 28408839
2016 Regulation of CpG methylation by Dnmt and Tet in pluripotent stem cells. The Journal of reproduction and development 20 27151232
2016 Placental expression of DNA methyltransferase 1 (DNMT1): Gender-specific relation with human placental growth. Placenta 20 27871462
2012 Non-catalytic functions of DNMT1. Epigenetics 20 22395459
2024 Tunable DNMT1 degradation reveals DNMT1/DNMT3B synergy in DNA methylation and genome organization. The Journal of cell biology 19 38376465
2018 S-allylcysteine suppresses ovarian cancer cell proliferation by DNA methylation through DNMT1. Journal of ovarian research 19 29759079
2019 Epigenetic factors Dnmt1 and Uhrf1 coordinate intestinal development. Developmental biology 18 31394080
2018 DNMT1 regulates expression of MHC class I in post-mitotic neurons. Molecular brain 18 29970123
2015 Biochemical characterization of maintenance DNA methyltransferase DNMT-1 from silkworm, Bombyx mori. Insect biochemistry and molecular biology 18 25623240
2023 Inhibition of DNMT1 methyltransferase activity via glucose-regulated O-GlcNAcylation alters the epigenome. eLife 17 37470704

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