Affinage

DNMT1

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

Round 2 corrected
Length
1616 aa
Mass
183.2 kDa
Annotated
2026-04-28
130 papers in source corpus 39 papers cited in narrative 39 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

DNMT1 is the principal maintenance DNA methyltransferase in mammals, responsible for copying CpG methylation patterns onto the newly synthesized strand during DNA replication and thereby ensuring epigenetic inheritance across cell divisions (PMID:3210246, PMID:11932749). It is recruited to replication forks through direct interaction with PCNA and, critically, through UHRF1, which recognizes hemimethylated CpG sites via its SRA domain and ubiquitylates histone H3 at K18/K23 to engage a DNMT1 ubiquitin-interacting motif; the RFTS domain autoinhibits DNMT1 until it binds ubiquitylated H3 and H3K9me3, while the BAH1 domain reads H4K20me3, together enabling allosteric activation via a toggle-helix mechanism resolved by cryo-EM (PMID:17673620, PMID:26065575, PMID:32675241, PMID:33941775, PMID:36414620). DNMT1 stability is regulated by K142 methylation (read by L3MBTL3 to recruit CRL4-DCAF5 for proteasomal degradation), KG-linker acetylation, and AMPK-mediated phosphorylation that directly inhibits catalytic activity; its function extends beyond catalysis through formation of repressive complexes with HDAC1/2, DMAP1, Rb/E2F1, and EZH2 that silence target genes, and its activity is modulated by locus-specific RNAs and pUG-fold structured RNAs that competitively block hemimethylated DNA binding (PMID:29691401, PMID:28143904, PMID:10615135, PMID:10888886, PMID:16357870, PMID:24107992, PMID:36574982). Mutations in the DNMT1 targeting sequence domain cause hereditary sensory autonomic neuropathy with dementia and hearing loss (HSAN1E) (PMID:23365052).

Mechanistic history

Synthesis pass · year-by-year structured walk · 14 steps
  1. 1988 High

    Cloning of Dnmt1 revealed the first mammalian DNA methyltransferase architecture — a large protein with a regulatory N-terminal domain and a C-terminal catalytic domain homologous to bacterial cytosine-5 methyltransferases — resolving the molecular identity of the maintenance methylation machinery.

    Evidence cDNA cloning/sequencing of mouse Dnmt1 with in vitro antibody inhibition assay

    PMID:3210246

    Open questions at the time
    • No information on substrate preference (hemimethylated vs unmethylated)
    • N-terminal regulatory mechanism unknown
    • No structural data
  2. 1997 High

    Discovery that DNMT1 directly binds PCNA and localizes to replication foci established the mechanistic basis for coupling maintenance methylation to DNA replication, answering how methylation patterns are faithfully copied each cell cycle.

    Evidence Co-immunoprecipitation, domain mapping (aa 163–174), replication focus imaging in human cells

    PMID:9302295

    Open questions at the time
    • PCNA interaction alone insufficient for full recruitment specificity
    • No hemimethylated DNA-targeting factor identified yet
  3. 2000 High

    Identification of DNMT1 complexes with HDAC1/2, DMAP1, and Rb/E2F1 revealed that DNMT1 participates in transcriptional repression beyond its catalytic methyltransferase function, linking the methylation machinery directly to chromatin silencing and cell-cycle control.

    Evidence Co-immunoprecipitation, co-purification, transcriptional reporter assays across multiple independent studies

    PMID:10615135 PMID:10888872 PMID:10888886

    Open questions at the time
    • Whether repression requires catalytic activity or is scaffold-mediated not resolved
    • Genome-wide target repertoire of DNMT1 repressive complexes unknown
  4. 2002 High

    Genetic disruption of both DNMT1 and DNMT3b in human cancer cells eliminated >95% of genomic methylation, whereas single knockouts had modest effects, establishing that DNMT1 cooperates with de novo methyltransferases to maintain global methylation and is not solely sufficient.

    Evidence Gene targeting in HCT116 cells, bisulfite sequencing, methyltransferase activity assay

    PMID:11932749 PMID:12383256

    Open questions at the time
    • Mechanism of functional cooperation between DNMT1 and DNMT3b unclear
    • Relative contributions in different genomic contexts not defined
  5. 2005 High

    EZH2 was found to physically interact with DNMT1 and recruit it to Polycomb-repressed promoters for DNA methylation, establishing a direct mechanistic connection between Polycomb-mediated histone methylation and DNA methylation-based silencing.

    Evidence Co-immunoprecipitation, ChIP, bisulfite sequencing at EZH2 target genes

    PMID:16357870

    Open questions at the time
    • Whether EZH2-DNMT1 interaction is direct or bridged not fully resolved
    • Generality across cell types unclear
  6. 2007 High

    Two independent studies identified UHRF1 as the essential hemimethylated CpG reader that recruits DNMT1 to replication forks, solving the long-standing question of how DNMT1 specifically finds its substrate at newly replicated DNA; simultaneously, HP1 proteins were shown to bridge H3K9 methylation to DNMT1 recruitment.

    Evidence UHRF1 knockout ES cells/embryos with bisulfite sequencing; SRA domain binding assays; HP1-DNMT1 co-IP with in vitro chromatin methylation assays

    PMID:17470536 PMID:17673620 PMID:17994007

    Open questions at the time
    • Mechanism by which UHRF1 hands off hemimethylated DNA to DNMT1 unknown
    • Whether UHRF1 ubiquitin ligase activity contributes not yet tested
  7. 2013 High

    Genome-wide RIP-seq revealed that locus-specific RNAs produced by active transcription bind DNMT1 and protect their loci from methylation, establishing a novel RNA-based mechanism for gene-selective regulation of DNMT1 activity.

    Evidence RNA immunoprecipitation deep sequencing, bisulfite sequencing at CEBPA and other loci

    PMID:24107992

    Open questions at the time
    • RNA-binding site on DNMT1 not structurally defined
    • Unclear how RNA inhibition is restricted to cognate loci in vivo
  8. 2015 High

    Discovery that UHRF1 ubiquitylates histone H3 at K18 via its RING domain, and that DNMT1 contains a UIM that recognizes ubiquitylated H3, resolved the molecular handoff mechanism — UHRF1 does not simply recruit DNMT1 by protein-protein interaction but creates a histone-based signal read by DNMT1's regulatory domain.

    Evidence Mass spectrometry identification of H3K18ub, systematic mutagenesis, functional complementation assays

    PMID:26065575

    Open questions at the time
    • Whether H3K23ub serves a redundant or distinct role not resolved
    • Structural basis of UIM-H3Ub recognition unknown
  9. 2015 High

    Crystallography of the DNMT1-USP7 complex showed that acetylation of the KG linker disrupts USP7 binding and promotes DNMT1 degradation, revealing a post-translational switch coupling DNMT1 stability to its acetylation state — though subsequent work questioned the physiological importance of USP7 for DNMT1 stability in somatic cells.

    Evidence 2.9 Å crystal structure, mutagenesis, HDAC inhibitor treatment; contradicted by analysis in USP7-null cells

    PMID:25960197 PMID:29482658

    Open questions at the time
    • Physiological significance of USP7-DNMT1 axis disputed
    • Context-dependent roles (development vs somatic) not defined
  10. 2018 High

    Identification of the K142 methylation-L3MBTL3-CRL4(DCAF5) degradation pathway, opposed by LSD1 demethylation and PHF20L1 protection, defined a complete writer-reader-eraser circuit controlling DNMT1 protein turnover and global DNA methylation levels.

    Evidence Co-immunoprecipitation, mass spectrometry, L3MBTL3 knockout mice with global methylation measurement

    PMID:29691401

    Open questions at the time
    • How K142 methylation is cell-cycle regulated unknown
    • Writer enzyme for K142 methylation not identified
  11. 2020 High

    Structural and functional characterization of the RFTS domain as a dual reader of H3K9me3 and H3 ubiquitylation explained how DNMT1 is allosterically activated at heterochromatin — RFTS autoinhibits the catalytic domain until it engages these marks, answering how DNMT1 activity is spatially restricted.

    Evidence Crystal structure of RFTS-H3K9me3 complex, binding assays, mutagenesis, global methylation and localization in stem cells

    PMID:32675241

    Open questions at the time
    • Quantitative contribution of each mark to activation kinetics unknown
    • How RFTS release is coordinated with DNA engagement not resolved
  12. 2021 High

    Discovery that the BAH1 domain reads H4K20me3 added a third histone modification input to DNMT1 targeting, explaining how DNMT1 achieves heterochromatin-specific activity — particularly at LINE-1 retrotransposons — through multivalent histone code readout cooperating with RFTS-mediated activation.

    Evidence Structural biology, mutagenesis, genome-wide methylation profiling showing LINE-1 hypomethylation upon BAH1 disruption

    PMID:33941775

    Open questions at the time
    • Whether BAH1-H4K20me3 directly contributes to allosteric activation or only targeting not distinguished
    • Contribution at euchromatic sites unknown
  13. 2022 High

    Cryo-EM of DNMT1 in complex with hemimethylated DNA and ubiquitinated H3 revealed a toggle-helix mechanism in which a conserved α-helix in the RFTS-CXXC linker displaces an autoinhibitory element, allowing the catalytic domain to adopt an active conformation — providing the first complete structural model of DNMT1 activation.

    Evidence Cryo-EM structure determination with mutagenesis and functional activity assays

    PMID:36414620

    Open questions at the time
    • Dynamics of conformational switching during replication fork progression not captured
    • Whether toggle mechanism operates identically in vivo on nucleosomal substrates unclear
  14. 2022 Medium

    Identification of pUG-fold RNA as a potent DNMT1 inhibitor that competes with hemimethylated DNA added structural specificity to the RNA-mediated regulation of DNMT1, extending beyond locus-specific transcripts to a defined RNA structural motif.

    Evidence In vitro RNA binding and activity assays with pUG-fold RNA competitors

    PMID:36574982

    Open questions at the time
    • In vivo significance of pUG-fold RNA inhibition not demonstrated
    • Structural basis of DNMT1-pUG interaction not resolved
    • Relevance to specific genomic loci unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • Outstanding questions include the identity of the K142 methyltransferase, the in vivo structural dynamics of DNMT1 activation at the replication fork on nucleosomal substrates, and the physiological scope and genomic targets of RNA-mediated DNMT1 inhibition.
  • K142 writer enzyme unknown
  • No replication fork-coupled structural data
  • Genome-wide mapping of pUG-fold RNA regulatory sites not performed

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016740 transferase activity 6 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
Localization
GO:0005634 nucleus 5 GO:0005694 chromosome 4
Pathway
R-HSA-4839726 Chromatin organization 5 R-HSA-74160 Gene expression (Transcription) 4 R-HSA-1640170 Cell Cycle 3 R-HSA-1643685 Disease 3 R-HSA-69306 DNA Replication 3
Partners
DMAP1EZH2HDAC1HDAC2L3MBTL3PCNAUHRF1USP7
Complex memberships
DNMT1-DMAP1-HDAC2DNMT1-Rb-E2F1-HDAC1DNMT1-UHRF1

Evidence

Reading pass · 39 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1988 Cloning and sequencing of the mouse Dnmt1 cDNA revealed a protein of 1573 amino acid residues with a C-terminal catalytic domain homologous to bacterial type II cytosine methyltransferases and a regulatory N-terminal domain; antibodies against the N-terminal region inhibited transmethylase activity in vitro. cDNA cloning, sequencing, in vitro inhibition assay with antibodies Journal of molecular biology High 3210246
1997 Human DNMT1 (MCMT) directly binds PCNA via amino acids 163–174 and co-localizes with PCNA at replication foci in intact cells; p21WAF1 disrupts this interaction, suggesting a regulatory link between cell-cycle control and DNA methylation. Co-immunoprecipitation, domain mapping, cell imaging at replication foci Science High 9302295
2000 DNMT1 associates with histone deacetylase (HDAC) activity in vivo; HDAC1 binds DNMT1 and can co-purify methyltransferase activity; a transcriptional repression domain in DNMT1 recruits HDAC activity, linking DNA methylation to histone deacetylation. Co-immunoprecipitation, co-purification, transcriptional repression assay Nature genetics High 10615135
2000 DNMT1 forms a complex with Rb, E2F1, and HDAC1 and represses transcription from E2F-responsive promoters, establishing a direct link between DNA methylation machinery and the Rb/E2F cell-cycle regulatory pathway. Co-purification, co-immunoprecipitation, transcriptional reporter assay Nature genetics High 10888886
2000 DNMT1 binds HDAC2 and a novel co-repressor DMAP1 at replication foci; DMAP1 has intrinsic repression activity and binds TSG101; HDAC2 joins the complex only in late S phase, providing a mechanism for heritable heterochromatin formation following replication. Co-immunoprecipitation, protein domain mapping, cell fractionation/imaging at replication foci Nature genetics High 10888872
2000 DNMT1 is essential for T cell development; conditional deletion in early double-negative thymocytes impaired TCRαβ+ cell survival and generated atypical CD8+TCRγδ+ cells; deletion in double-positive thymocytes impaired activation-induced proliferation but enhanced cytokine expression, demonstrating a non-redundant epigenetic regulatory role in T cell fate. Conditional knockout (Cre/loxP) in vivo, flow cytometry, gene expression analysis Immunity High 11728338
2002 DNMT1 and DNMT3b cooperatively maintain DNA methylation and gene silencing in human cancer cells; disruption of both enzymes nearly eliminated methyltransferase activity and reduced genomic DNA methylation by >95%, whereas individual knockouts had modest effects. Genetic disruption (gene targeting), bisulfite sequencing, methyltransferase activity assay Nature High 11932749
2002 Dnmt3a and Dnmt1 functionally cooperate in de novo methylation: Dnmt3a-mediated initial methylation stimulates Dnmt1 activity ~5-fold on the same substrate, without requiring direct physical interaction; Dnmt1 is also activated by pre-existing methyl groups on unmethylated DNA. In vitro methylation assay, sequential enzyme incubation, substrate pre-methylation experiments European journal of biochemistry High 12383256
2004 RGS6 interacts with DMAP1 and co-immunoprecipitates DNMT1 in a DMAP1-dependent manner; RGS6 inhibits the transcriptional repressor activity of DMAP1, placing RGS6 as a modulator of the DNMT1-DMAP1 repressive complex. Yeast two-hybrid, co-immunoprecipitation, domain mapping, transcriptional reporter assay The Journal of biological chemistry Medium 14734556
2004 Dnmt1 deficiency in mouse embryonic stem cells increases microsatellite instability at several loci, suggesting that Dnmt1 participates in mismatch repair or strand-discrimination during DNA replication. PCR-based microsatellite instability assay in Dnmt1-null ES cells Oncogene Medium 15378011
2005 EZH2 interacts with DNMT1, DNMT3A, and DNMT3B within PRC2/3 complexes; binding of DNMTs to EZH2-repressed gene promoters depends on EZH2 presence; EZH2 is required for DNA methylation at its target promoters, establishing a mechanistic link between Polycomb silencing and DNA methylation. Co-immunoprecipitation, chromatin immunoprecipitation, bisulfite genomic sequencing Nature High 16357870
2006 Bmi1 directly interacts with DMAP1, which bridges to DNMT1, forming a ternary Bmi1-DMAP1-DNMT1 complex at PRC1 target loci; loss of Dmap1 binding correlates with derepression of Hox genes in Bmi1-null cells. Co-immunoprecipitation, chromatin immunoprecipitation, knockdown/knockout gene expression analysis Biochemical and biophysical research communications Medium 17214966
2007 UHRF1 (NP95/ICBP90) is required for maintaining DNA methylation in mammals; UHRF1 colocalizes with DNMT1 throughout S phase, directly interacts with DNMT1, and its SRA domain preferentially binds hemimethylated CpG sites—the physiological substrate of DNMT1—suggesting UHRF1 recruits DNMT1 to hemimethylated DNA. Co-immunoprecipitation, fluorescence microscopy colocalization, SRA domain binding assay, UHRF1 knockout cells Science High 17673620
2007 Np95 (Uhrf1) forms complexes with Dnmt1 and mediates loading of Dnmt1 to replicating heterochromatic regions; Np95-deficient ES cells and embryos show global and locus-specific loss of DNA methylation and derepression of retrotransposons and imprinted genes. Co-immunoprecipitation, live-cell imaging, Np95 knockout ES cells and embryos, bisulfite sequencing Nature High 17994007
2007 HP1 family members mediate communication between histone and DNA methyltransferases: G9a-mediated H3K9 methylation creates a binding platform for HP1α/β/γ, which interact directly with DNMT1; this interaction increases DNA methylation on DNA and chromatin templates in vitro and is required for silencing of the Survivin gene in vivo. In vitro methylation assay on chromatin templates, co-immunoprecipitation, reporter gene assay in DNMT1-null cells, ChIP Genes & development High 17470536
2010 Kcnq1ot1 lncRNA recruits Dnmt1 to somatic differentially methylated regions (DMRs) via direct interaction with Dnmt1; deletion of an 890-bp silencing domain in Kcnq1ot1 reduces Dnmt1 interaction and selectively relaxes imprinting of ubiquitously imprinted genes with loss of DNA methylation at somatic DMRs. Knockout mouse, RNA immunoprecipitation, bisulfite sequencing, allele-specific expression analysis Development High 20573698
2010 Conditional double knockout of Dnmt1 and Dnmt3a in forebrain excitatory neurons impairs long-term synaptic plasticity in hippocampal CA1 and causes deficits in learning and memory; neuronal gene expression is deregulated including MHC class I genes, demonstrating a role for DNMT1-maintained methylation in adult neuronal function. Conditional knockout (Cre/loxP), electrophysiology, behavioral testing, gene expression profiling, bisulfite sequencing Nature neuroscience High 20228804
2011 Uhrf1 and Dnmt1 are required for lens development in zebrafish; in the absence of Uhrf1 or catalytically active Dnmt1, lens epithelial cells show altered gene expression, reduced proliferation, and apoptosis, demonstrating a lens-autonomous (but not strictly cell-autonomous) requirement for DNA methylation maintenance. Zebrafish genetic mutants, lens transplant experiments, immunofluorescence, gene expression analysis Developmental biology High 21126517
2013 Active transcription produces locus-specific RNAs (e.g., from the CEBPA locus) that bind DNMT1 and prevent methylation of that gene locus; deep sequencing of DNMT1-associated transcripts identified numerous such RNAs genome-wide, suggesting RNA-mediated gene-selective regulation of DNMT1 activity. RNA immunoprecipitation deep sequencing (RIP-seq), genome-wide methylation profiling, bisulfite sequencing, DNMT1-RNA binding assays Nature High 24107992
2013 Mutations in the targeting sequence (TS) domain of DNMT1 (e.g., Tyr495Cys, Tyr495His in exons 20–21) cause hereditary sensory autonomic neuropathy with dementia and hearing loss (HSAN1E), establishing Tyr495 as a mutation hotspot and implicating the TS domain in DNA substrate binding. Sequencing of DNMT1 exons in patient cohorts, clinical phenotyping Neurology Medium 23365052
2015 Crystal structure of DNMT1 bound to 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; acetylation of KG linker Lys residues impairs DNMT1–USP7 interaction and promotes DNMT1 degradation; HDAC inhibitor treatment increases acetylated DNMT1 and decreases total DNMT1. Crystal structure determination, mutagenesis, co-immunoprecipitation, HDAC inhibitor treatment with Western blot Nature communications High 25960197
2015 DNMT1 contains a ubiquitin interacting motif (UIM) in its N-terminal regulatory domain that binds ubiquitinated histone H3 tails; UHRF1 RING domain ubiquitin ligase activity is required for maintenance DNA methylation; UHRF1 PHD domain binding to unmodified H3R2 is required for H3K18 ubiquitination and subsequent DNMT1 UIM-dependent chromatin recruitment. Systematic mutagenesis, mass spectrometry identification of H3K18 ubiquitination, functional complementation assays, bioinformatic motif identification Cell research High 26065575
2015 Deletion of DNMT1 in human embryonic stem cells causes rapid global loss of DNA methylation followed by extensive cell death, demonstrating that DNMT1 is essential for human ESC viability in a manner distinct from mouse ESCs. CRISPR/Cas9 gene editing, doxycycline-regulated rescue line, whole-genome bisulfite sequencing Nature genetics High 25822089
2017 AMPK phosphorylates DNMT1 at a consensus motif, directly inhibiting its activity; this inhibition is potentiated by increased DNMT1 interaction with RBBP7; AMPK activation or pulsatile shear stress triggers decreased cytosine methylation at mitochondrial biogenesis gene promoters in endothelial cells, effects requiring AMPKα2. AMPK consensus motif identification, in vitro phosphorylation assay, co-immunoprecipitation, pharmacological AMPK activation in cells and mouse aortas Science signaling High 28143904
2017 2-hydroxyglutarate (2-HG) directly binds DNMT1 and stimulates its association with the RIP3 promoter, inducing hypermethylation that reduces RIP3 expression and impairs necroptosis in IDH1/2-mutant cells. DNMT1 binding assay with 2-HG, ChIP of DNMT1 at RIP3 promoter, bisulfite sequencing, IDH1 knockin MEFs Cell reports High 28564603
2017 DNMT1 isoform 3 (not isoform 1 as previously reported) localizes to mitochondria and methylates CpG regions in the mitochondrial genome; overexpression of isoform 3 affects mitochondrial function; oxidative/nutritional stress downregulates this isoform, causing mitochondrial hypomethylation. Ectopic expression with fluorescence imaging, mitochondrial fractionation, CpG methylation assay on mtDNA Scientific reports Medium 28484249
2018 Stella (Dppa3) prevents ectopic nuclear accumulation of UHRF1, which in turn prevents DNMT1 mislocalization to the nucleus in oocytes; genetic analysis confirmed that UHRF1 and DNMT1 are responsible for aberrant de novo DNA methylation in Stella-deficient oocytes, causing oocyte hypermethylation and impaired zygotic genome activation. Knockout mouse, immunofluorescence for UHRF1/DNMT1 localization, genome-wide bisulfite sequencing, genetic epistasis Nature High 30487604
2018 DNMT1 modulates cortical interneuron morphology by repressing Pak6 through a mechanism involving interaction with the PRC2 core enzyme EZH2, which mediates repressive H3K27me3 at Pak6 regulatory regions; this function operates independently of DNMT1's direct DNA methylation activity. Dnmt1 knockdown in interneurons, EZH2 inhibitor treatment, H3K27me3 ChIP, siRNA rescue, morphological analysis Epigenetics Medium 29912614
2018 Methylated DNMT1 at Lys142 is recognized by the methyl-binding protein L3MBTL3, which recruits the CRL4DCAF5 ubiquitin ligase to degrade DNMT1; LSD1 demethylates K142 to stabilize DNMT1 primarily in S phase; PHF20L1 also prevents DNMT1 degradation; L3MBTL3 deletion in mice increases DNMT1 protein and global DNA methylation. Co-immunoprecipitation, ubiquitin ligase identification, mass spectrometry, mouse knockout, global methylation measurement Nature communications High 29691401
2018 Kindlin-2 directly interacts with DNMT1 and increases its protein stability; this interaction promotes DNMT1 occupancy at the E-cadherin promoter CpG islands, leading to E-cadherin silencing and enhanced breast cancer cell proliferation and migration. Co-immunoprecipitation, chromatin immunoprecipitation, DNMT inhibitor experiments, transgenic mouse model International journal of biochemistry & cell biology Medium 30287284
2019 SET8 (a protein methyltransferase) methylates UHRF1 at K385, triggering its ubiquitin-dependent degradation, and also promotes degradation of DNMT1 through the UHRF1 axis; LSD1 opposes SET8 by demethylating UHRF1 and stabilizing both UHRF1 and DNMT1; SET8-mediated UHRF1 downregulation in G2/M suppresses DNMT1-mediated post-replicative methylation. In vitro methylation assay, co-immunoprecipitation, ubiquitination assay, global methylation measurement Nucleic acids research High 31400111
2019 YAP1-TEAD transcriptional complex directly drives DNMT1 expression; DNMT1 acts downstream of NOTCH-YAP1/TEAD signaling to repress hepatocyte-specific genes (regulated by HNF4α, HNF1α, C/EBPα/β) via promoter methylation, directing hepatocyte-to-biliary epithelial cell reprogramming and intrahepatic cholangiocarcinoma development; DNMT1 loss prevents NOTCH/YAP1-dependent cholangiocarcinogenesis. ChIP-seq, loss- and gain-of-function studies, in vivo tumor model, chromatin immunoprecipitation Gastroenterology High 35550144
2020 The RFTS domain of DNMT1 acts as a specific reader for H3K9me3 and ubiquitylated H3 (H3Ub), with a recognition mode distinct from canonical trimethyl-lysine readers; disruption of RFTS–H3K9me3Ub interaction impairs DNMT1 localization in stem cells and profoundly reduces global DNA methylation and genomic stability. Crystal structure of RFTS-H3K9me3 complex, biochemical binding assays, mutagenesis, DNMT1 localization in stem cells, global methylation measurement PNAS High 32675241
2021 DNMT1's first BAH domain (BAH1) specifically recognizes trimethylated H4K20 (H4K20me3) at heterochromatin; engagement of DNMT1BAH1–H4K20me3 ensures heterochromatin targeting of DNMT1 and DNA methylation at LINE-1 retrotransposons; BAH1 cooperates with RFTS domain readout of H3K9me3 and H3 ubiquitylation for allosteric activation of DNMT1 activity. Structural biology, biochemical binding assays, mutagenesis, cell-based methylation and localization assays, genome-wide methylation profiling Nature communications High 33941775
2022 Cryo-EM structure of human DNMT1 bound to hemimethylated DNA and ubiquitinated histone H3 revealed a previously unstudied linker between the RFTS and CXXC domains containing a conserved α-helix that engages a 'Toggle' pocket, displacing an inhibitory linker and allowing the DNA recognition helix to adopt the active conformation; activation involves large-scale reorganization of the inhibitory RFTS and CXXC domains. Cryo-EM structure determination, mutagenesis, functional activity assays Nature communications High 36414620
2022 DNMT1 exhibits strong and specific affinity for GU-rich RNAs forming a pUG-fold (noncanonical G-quadruplex); pUG-fold RNAs inhibit DNMT1 activity by blocking binding of hemimethylated DNA; DNMT1 also binds its own nuclear mRNA, suggesting multiple RNA-binding modes regulate its activity. In vitro RNA binding assays, DNMT1 activity assay with RNA competitors, RNA immunoprecipitation RNA Medium 36574982
2023 GSK-3484862 (a non-nucleoside DNMT1-selective inhibitor) triggers rapid, proteasome-dependent DNMT1 protein degradation in cancer cells and mESCs, leading to global hypomethylation; in mESCs, this requires UHRF1 and its E3 ubiquitin ligase activity; depletion and hypomethylation are reversible after drug removal. Western blotting of protein levels, proteasome inhibitor rescue, UHRF1 knockout mESCs, global methylation assay NAR cancer High 37206360
2012 Key enzyme–DNA contacts at the target cytosine and the guanine:5mC base pair flanking the CpG site are critical for Dnmt1 catalytic activity, as revealed by mutagenesis guided by the crystal structure; the non-target strand Gua–base contact is not required and its replacement by Ade actually stimulates activity. In vitro methylation assay with mutagenesis guided by crystal structure FEBS letters Medium 22641038
2018 Multiple independent lines of evidence indicate that USP7 interaction with DNMT1's GK repeats does not play a major role in stabilizing DNMT1 protein in somatic cells: DNMT1 is present at normal levels in cells lacking detectable USP7; GK→GQ substitution preventing Lys acetylation does not affect DNMT1 stability; DNMT1 is not degraded after S phase in cycling cells. Western blot in USP7-null cells, GK→GQ substitution mutant analysis, replication focus imaging Epigenetics & chromatin Medium 29482658

Source papers

Stage 0 corpus · 130 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2020 A SARS-CoV-2 protein interaction map reveals targets for drug repurposing. Nature 3411 32353859
2006 Global, in vivo, and site-specific phosphorylation dynamics in signaling networks. Cell 2861 17081983
2005 The Polycomb group protein EZH2 directly controls DNA methylation. Nature 1727 16357870
2005 A human protein-protein interaction network: a resource for annotating the proteome. Cell 1704 16169070
2002 Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. Proceedings of the National Academy of Sciences of the United States of America 1479 12477932
2000 The DNA methyltransferases of mammals. Human molecular genetics 1470 11005794
2009 Defining the human deubiquitinating enzyme interaction landscape. Cell 1282 19615732
2006 Substrate and functional diversity of lysine acetylation revealed by a proteomics survey. Molecular cell 1260 16916647
2004 Large-scale characterization of HeLa cell nuclear phosphoproteins. Proceedings of the National Academy of Sciences of the United States of America 1159 15302935
2015 The BioPlex Network: A Systematic Exploration of the Human Interactome. Cell 1118 26186194
2001 A critical role for Dnmt1 and DNA methylation in T cell development, function, and survival. Immunity 1081 11728338
2007 UHRF1 plays a role in maintaining DNA methylation in mammalian cells. Science (New York, N.Y.) 1080 17673620
2015 A human interactome in three quantitative dimensions organized by stoichiometries and abundances. Cell 1015 26496610
2002 DNMT1 and DNMT3b cooperate to silence genes in human cancer cells. Nature 1014 11932749
2007 The SRA protein Np95 mediates epigenetic inheritance by recruiting Dnmt1 to methylated DNA. Nature 988 17994007
2003 Suv39h-mediated histone H3 lysine 9 methylation directs DNA methylation to major satellite repeats at pericentric heterochromatin. Current biology : CB 953 12867029
2006 Polycomb-mediated methylation on Lys27 of histone H3 pre-marks genes for de novo methylation in cancer. Nature genetics 934 17200670
2005 Nucleolar proteome dynamics. Nature 934 15635413
2005 Transcriptional maps of 10 human chromosomes at 5-nucleotide resolution. Science (New York, N.Y.) 881 15790807
2007 Covalent modification of DNA regulates memory formation. Neuron 879 17359920
2000 DNMT1 binds HDAC2 and a new co-repressor, DMAP1, to form a complex at replication foci. Nature genetics 843 10888872
2018 VIRMA mediates preferential m6A mRNA methylation in 3'UTR and near stop codon and associates with alternative polyadenylation. Cell discovery 829 29507755
2010 Dnmt1 and Dnmt3a maintain DNA methylation and regulate synaptic function in adult forebrain neurons. Nature neuroscience 785 20228804
2000 DNA methyltransferase Dnmt1 associates with histone deacetylase activity. Nature genetics 766 10615135
1997 Human DNA-(cytosine-5) methyltransferase-PCNA complex as a target for p21WAF1. Science (New York, N.Y.) 756 9302295
2000 DNMT1 forms a complex with Rb, E2F1 and HDAC1 and represses transcription from E2F-responsive promoters. Nature genetics 755 10888886
2003 Complete sequencing and characterization of 21,243 full-length human cDNAs. Nature genetics 754 14702039
1988 Cloning and sequencing of a cDNA encoding DNA methyltransferase of mouse cells. The carboxyl-terminal domain of the mammalian enzymes is related to bacterial restriction methyltransferases. Journal of molecular biology 733 3210246
2021 Dual proteome-scale networks reveal cell-specific remodeling of the human interactome. Cell 705 33961781
1999 The human DNA methyltransferases (DNMTs) 1, 3a and 3b: coordinate mRNA expression in normal tissues and overexpression in tumors. Nucleic acids research 669 10325416
2013 DNMT1-interacting RNAs block gene-specific DNA methylation. Nature 405 24107992
2015 Targeted disruption of DNMT1, DNMT3A and DNMT3B in human embryonic stem cells. Nature genetics 379 25822089
2018 A circular RNA circ-DNMT1 enhances breast cancer progression by activating autophagy. Oncogene 268 29973691
2007 Functional cooperation between HP1 and DNMT1 mediates gene silencing. Genes & development 260 17470536
2010 Kcnq1ot1 noncoding RNA mediates transcriptional gene silencing by interacting with Dnmt1. Development (Cambridge, England) 225 20573698
2018 Stella safeguards the oocyte methylome by preventing de novo methylation mediated by DNMT1. Nature 222 30487604
2017 AMPK promotes mitochondrial biogenesis and function by phosphorylating the epigenetic factors DNMT1, RBBP7, and HAT1. Science signaling 203 28143904
2002 Dnmt3a and Dnmt1 functionally cooperate during de novo methylation of DNA. European journal of biochemistry 202 12383256
2015 DNA methylation requires a DNMT1 ubiquitin interacting motif (UIM) and histone ubiquitination. Cell research 189 26065575
2019 Inhibition of a G9a/DNMT network triggers immune-mediated bladder cancer regression. Nature medicine 154 31270502
2020 DNMT1: A key drug target in triple-negative breast cancer. Seminars in cancer biology 152 32461152
2006 Aberrant expression of deoxyribonucleic acid methyltransferases DNMT1, DNMT3A, and DNMT3B in women with endometriosis. Fertility and sterility 145 17081533
2019 Intestinal PPARα Protects Against Colon Carcinogenesis via Regulation of Methyltransferases DNMT1 and PRMT6. Gastroenterology 143 31154022
2015 Molecular mechanism for USP7-mediated DNMT1 stabilization by acetylation. Nature communications 126 25960197
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