Affinage

DMAP1

DNA methyltransferase 1-associated protein 1 · UniProt Q9NPF5

Length
467 aa
Mass
53.0 kDa
Annotated
2026-06-09
20 papers in source corpus 15 papers cited in narrative 15 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

DMAP1 is a chromatin-associated co-repressor that couples DNA methylation to histone modification and DNA-damage signaling across S phase and beyond (PMID:10888872, PMID:20864525). It binds directly to the non-catalytic N-terminus of DNMT1, an interaction that targets it to replication foci throughout S phase and nucleates a repressive transcription complex into which HDAC2 is recruited during late S phase (PMID:10888872); DMAP1 itself carries intrinsic transcriptional repressive activity and directly stimulates DNMT1 methyltransferase activity, sustaining CpG methylation at promoters such as p16 and at imprinted loci (PMID:10888872, PMID:20864525, PMID:21383065). Genetic loss of DMAP1 is lethal at preimplantation and abolishes maintenance methylation, consistent with its dual membership in the DNMT1 and TIP60-p400 complexes (PMID:21383065). Within the TIP60-p400 acetyltransferase context DMAP1 is required for H4K16 acetylation and downstream ATM activation, the G2/M checkpoint, and radioresistance after DNA damage, acting upstream of acetylation as shown by HDAC-inhibitor rescue (PMID:23318425); it is independently recruited to damage sites where it binds and stabilizes PCNA to enable efficient repair and restrain hyper-recombination (PMID:19845771, PMID:20864525). DMAP1 also represses transcription through interactions with HDAC1 and with the MAT1 subunit of CAK/TFIIH, inhibiting RNA polymerase II CTD phosphorylation and gating cell-cycle transitions (PMID:17371848, PMID:20920467). In mitotic stress, p38-driven Bub3-Ser211 phosphorylation promotes a DMAP1/Bub3 complex recruited by TAp73 to methylate and silence the anti-apoptotic gene BCL2L1, while c-Src phosphorylation of DMAP1 at Tyr246 blocks this complex to confer stress resistance in pancreatic cancer (PMID:30553276). In embryonic stem cells DMAP1 occupies differentiation-commitment gene promoters and cooperates with Polycomb proteins to set histone bivalency (PMID:32403252).

Mechanistic history

Synthesis pass · year-by-year structured walk · 13 steps
  1. 2000 High

    Established DMAP1's founding identity: how is DNMT1-associated transcriptional repression organized, and what links DNA methylation machinery to histone deacetylation across S phase?

    Evidence Co-IP, yeast two-hybrid, transcription repression assays, and colocalization at replication foci

    PMID:10888872

    Open questions at the time
    • Structural basis of the DNMT1 N-terminus interaction not defined
    • Genomic targets of the complex not mapped at this stage
  2. 2004 Medium

    Extended the repressor network by identifying Daxx and RGS6 as DMAP1 partners that modulate its repressive output and stability, showing DMAP1 sits in regulatable transcriptional complexes.

    Evidence Yeast two-hybrid, reciprocal Co-IP, luciferase reporter assays, and protein-stability assays

    PMID:14734556 PMID:14978102

    Open questions at the time
    • Physiological contexts where Daxx/RGS6 control DMAP1 unclear
    • RGS6 GGL-domain interaction not structurally resolved
  3. 2007 High

    Defined a second, HDAC-independent repression route: DMAP1 binds MAT1 (CAK/TFIIH) and inhibits RNA Pol II CTD phosphorylation, plus binds HDAC1, showing repression operates through both deacetylation and transcription-machinery inhibition.

    Evidence Yeast two-hybrid, Co-IP, in vitro kinase assay, and dominant-negative HDAC1 competition

    PMID:17371848

    Open questions at the time
    • Promoter contexts using the MAT1 versus HDAC route not delineated
    • In vivo significance of CTD inhibition not tested
  4. 2009 High

    Showed DMAP1 has a direct DNA-repair function beyond transcription: it is recruited to damage sites and stabilizes PCNA accumulation, with PCNA-binding mutants failing to rescue repair.

    Evidence shRNA knockdown, immunofluorescence, Co-IP, and binding-deficient mutant rescue

    PMID:19845771

    Open questions at the time
    • Which repair pathway PCNA stabilization serves not fully specified
    • Relationship to the DNMT1 versus TIP60 complex at damage sites unresolved
  5. 2010 High

    Demonstrated DMAP1 directly activates DNMT1 enzymatic activity and links methylation to recombination, methylating both p16 and HR repair products and restraining HR.

    Evidence In vitro methylation assay, shRNA, bisulfite sequencing, HR reporter, and ChIP

    PMID:20864525

    Open questions at the time
    • Mechanism coupling methylation to HR suppression not defined
    • Whether enzymatic stimulation requires the full complex unknown
  6. 2010 Medium

    Connected DMAP1 to cell-cycle timing: overexpression delays G1/S and G2/M via MAT1-dependent inhibition of CAK-mediated CDK1 phosphorylation.

    Evidence Overexpression, co-expression rescue, flow cytometry, and kinase assay

    PMID:20920467

    Open questions at the time
    • Endogenous-level requirement for cell-cycle control not established
    • Overexpression artefact possibility not excluded
  7. 2011 High

    Established the developmental requirement and dual complex membership: DMAP1 is part of both TIP60-p400 and DNMT1 complexes, with null mice dying at preimplantation and losing imprinted-gene methylation.

    Evidence Genetic null allele, Co-IP, and bisulfite sequencing of imprinted genes

    PMID:21383065

    Open questions at the time
    • Whether lethality reflects TIP60-p400 or DNMT1 function not separable
    • Tissue-specific roles not addressed by constitutive null
  8. 2013 High

    Placed DMAP1 upstream of the DNA-damage response chromatin signal: it is required for TIP60-dependent H4K16 acetylation, ATM activation, and the G2/M checkpoint after irradiation.

    Evidence shRNA, overexpression, ATM substrate phosphorylation, H4K16ac, HAT activity, and HDAC-inhibitor rescue

    PMID:23318425

    Open questions at the time
    • Direct biochemical role of DMAP1 in HAT catalysis versus recruitment unclear
    • Link to its PCNA-stabilizing repair function not integrated
  9. 2014 Medium

    Revealed a conserved innate-immune role: Drosophila DMAP1 associates with Relish, Akirin and BAP55 and is needed for antimicrobial peptide induction in the IMD pathway.

    Evidence Co-IP, RNAi in S2 cells and in vivo, and epistasis analysis

    PMID:24947515

    Open questions at the time
    • Whether mammalian DMAP1 has an equivalent NF-kB role untested
    • Molecular step DMAP1 performs in the pathway undefined
  10. 2018 High

    Defined a phospho-switch controlling apoptosis: p38-phosphorylated Bub3 forms a DMAP1/Bub3 complex recruited by TAp73 to methylate and silence BCL2L1, while c-Src phosphorylation of DMAP1-Tyr246 disrupts this to confer mitotic-stress resistance.

    Evidence Co-IP, phospho-site mutagenesis, ChIP, bisulfite sequencing, kinase assays, and in vivo tumor models

    PMID:30553276

    Open questions at the time
    • Generality beyond pancreatic cancer not tested
    • How TAp73 selects the BCL2L1 locus not detailed
  11. 2020 Medium

    Showed DMAP1 shapes stem-cell fate by occupying differentiation-commitment promoters and cooperating with Polycomb proteins to set histone bivalency and poising.

    Evidence ChIP and gene-expression analysis during ESC differentiation with PcG interaction data

    PMID:32403252

    Open questions at the time
    • Direct biochemical PcG interaction not fully mapped
    • Causal contribution to bivalency versus correlation unresolved
  12. 2026 Medium

    Linked DMAP1 loss to genome instability and tumor immunity: deficiency retards replication forks, induces endogenous DNA damage, and activates IFN-mediated anti-tumor responses in lung cancer.

    Evidence CRISPR knockout screen, replication fork and DNA damage assays, IFN pathway and immune-cell analyses

    PMID:41904944

    Open questions at the time
    • Mechanism connecting fork stress to IFN activation not detailed
    • Whether this reflects methylation or TIP60 function unclear
  13. 2025 Low

    Implicated DMAP1 in transposon silencing during spermatogenesis: DAXX-DMAP1 interaction maintains LINE1/ERV DNA methylation in meiotic germ cells.

    Evidence Conditional Daxx knockout, Co-IP, and DNA methylation and transposon expression analysis (preprint)

    PMID:bio_10.1101_2025.07.24.666258

    Open questions at the time
    • Mechanistic link between DAXX-DMAP1 binding and LINE1 methylation inferred, not reconstituted
    • Preprint, not peer-reviewed
    • Direct DMAP1 requirement (versus DAXX alone) not isolated

Open questions

Synthesis pass · forward-looking unresolved questions
  • How DMAP1 partitions its activities between the DNMT1 methylation complex and the TIP60-p400 acetyltransferase complex at any given locus or repair site, and whether these are coordinated or competing, remains unresolved.
  • No structural model of DMAP1 in either complex
  • Locus-level switch between methylation and acetylation roles undefined
  • No reconstitution distinguishing direct catalysis-stimulation from scaffolding

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 3 GO:0098772 molecular function regulator activity 3 GO:0140110 transcription regulator activity 3 GO:0003677 DNA binding 2
Localization
GO:0000228 nuclear chromosome 3 GO:0005634 nucleus 2
Pathway
R-HSA-1640170 Cell Cycle 3 R-HSA-4839726 Chromatin organization 3 R-HSA-73894 DNA Repair 2 R-HSA-74160 Gene expression (Transcription) 2 R-HSA-5357801 Programmed Cell Death 1
Partners
DAXXDNMT1HDAC1HDAC2MAT1PCNARGS6TSG101
Complex memberships
DNMT1-DMAP1-HDAC2 repressor complexTIP60-p400 histone acetyltransferase complex

Evidence

Reading pass · 15 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2000 DMAP1 was identified as a novel co-repressor that binds directly to the non-catalytic amino terminus of DNMT1, and together with HDAC2 forms a repressive transcription complex. DMAP1 has intrinsic transcription repressive activity and binds the transcriptional co-repressor TSG101. DMAP1 is targeted to replication foci through interaction with the far N terminus of DNMT1 throughout S phase; HDAC2 joins only during late S phase. Co-immunoprecipitation, yeast two-hybrid, transcription repression assays, immunofluorescence/colocalization at replication foci Nature genetics High 10888872
2004 DMAP1 interacts physically with Daxx (identified by yeast two-hybrid and confirmed by Co-IP); both proteins co-localize in the nucleus and form a complex with DNMT1. DMAP1 enhances Daxx-mediated repression of glucocorticoid receptor transcriptional activity. Daxx protects DMAP1 from protein degradation in vivo. Yeast two-hybrid screen, co-immunoprecipitation, luciferase reporter transcription assay, immunofluorescence colocalization, protein stability assay Journal of immunology Medium 14978102
2004 RGS6 interacts with DMAP1 via its GGL domain (a region distinct from the Gbeta5 binding region), and this interaction is mapped to the C-terminal domain of DMAP1. RGS6 co-immunoprecipitates DMAP1 and DNMT1 in a DMAP1-dependent manner. Co-expression of DMAP1 with RGS6L promotes nuclear migration of RGS6L. RGS6 inhibits the transcriptional repressor activity of DMAP1. Yeast two-hybrid screen, co-immunoprecipitation, deletion mutagenesis, GFP-localization, transcriptional repression assay The Journal of biological chemistry Medium 14734556
2007 DMAP1 (as MMTR) interacts with HDAC1 both in vitro and in vivo, contributing to transcriptional repression. Separately and independently, DMAP1 interacts with MAT1 (a subunit of CAK/TFIIH) through MAT1's coiled-coil domain, and DMAP1 inhibits phosphorylation of the RNA polymerase II CTD by TFIIH kinase in vitro. TSA (HDAC inhibitor) only partially rescues DMAP1 repression, and the MAT1-dependent pathway fully restores it. Yeast two-hybrid, co-immunoprecipitation, in vitro kinase assay, luciferase reporter assay, dominant-negative HDAC1 competition Molecular and cellular biology High 17371848
2009 Dmap1 is required for efficient DNA repair: upon DNA damage, Dmap1 is recruited to damaged sites where it forms complexes with γ-H2AX and PCNA. Depletion of Dmap1 abrogates stable accumulation of PCNA at DNA damage sites. Dmap1 mutants with reduced PCNA-binding capacity fail to rescue impaired DNA repair in Dmap1-depleted cells. Dmap1 knockdown leads to spontaneous double-strand breaks and p53-dependent growth arrest. shRNA knockdown, immunofluorescence/colocalization, co-immunoprecipitation, re-introduction of binding-deficient Dmap1 mutants, γ-H2AX foci assay Genes to cells High 19845771
2010 DMAP1 is a potent activator of DNMT1 methyltransferase activity in vitro (co-repressor function). Knockdown of DMAP1 reduces CpG methylation at the p16 tumor suppressor gene promoter in vivo, and also causes hypomethylation of homologous recombination (HR) repair products. DMAP1 is selectively enriched at recombinant GFP chromatin (site of HR repair) by ChIP. DMAP1-depleted cells show enhanced HR. In vitro DNA methylation assay, lentiviral shRNA knockdown, bisulfite sequencing, fluorescence-based HR reporter, chromatin immunoprecipitation (ChIP) The Journal of biological chemistry High 20864525
2010 DMAP1 (as MMTR) over-expression delays G1/S and G2/M cell cycle transitions; DMAP1 is required for inhibition of CAK kinase-mediated CDK1 phosphorylation via interaction with MAT1. Co-expression of MAT1 rescues the growth delay caused by DMAP1 over-expression. DMAP1 expression levels are modulated during cell cycle progression. Overexpression, co-expression rescue, cell cycle analysis (flow cytometry), kinase assay Biochemical and biophysical research communications Medium 20920467
2011 DMAP1 is a member of both the TIP60-p400 complex and the DNMT1s complex in mouse embryonic stem cells. DMAP1 null mice die during preimplantation (consistent with TIP60-p400 loss). DMAP1 interacts with DNMT1o when stably expressed in ES cells (detected by Co-IP), but this complex is not readily formed upon transient expression. Loss of DMAP1 causes loss of DNA methylation on imprinted genes, establishing that DMAP1-DNMT1s and DMAP1-DNMT1o interactions are required for maintenance methylation in development. Genetic knockout (null allele generation), co-immunoprecipitation, bisulfite sequencing of imprinted genes, stable vs. transient expression comparison Molecular and cellular biology High 21383065
2013 DMAP1 is required for ATM activation in response to ionizing radiation (IR) and hypotonic stress. DMAP1 knockdown impairs IR-induced ATM substrate phosphorylation, causes radiosensitivity, and impairs the G2/M checkpoint. Overexpression of DMAP1 increases IR-induced ATM substrate phosphorylation. DMAP1 associates with TIP60-dependent HAT activity; depletion reduces H4K16 acetylation after DNA damage. HDAC inhibitors rescue ATM signaling in DMAP1-depleted cells, placing DMAP1 upstream of H4K16 acetylation and ATM activation. shRNA knockdown, overexpression, IR treatment, ATM substrate phosphorylation assay, G2/M checkpoint assay, H4K16 acetylation assay, HDAC inhibitor rescue, HAT activity assay Oncogene High 23318425
2014 In Drosophila, DMAP1 interacts with the NF-κB transcription factor Relish and with Akirin and BAP55 (a SWI/SNF complex component), as shown by co-immunoprecipitation. Silencing of DMAP1 reduces E. coli-induced antimicrobial peptide expression. Epistatic analysis indicates DMAP1 acts in parallel or downstream of Relish in the IMD pathway. Co-immunoprecipitation, RNAi silencing in S2 cells and in vivo, antimicrobial peptide expression assay, epistasis analysis The Journal of biological chemistry Medium 24947515
2018 Mitotic arrest induces p38-dependent phosphorylation of Bub3 at Ser211, which promotes DMAP1/Bub3 complex formation. The DMAP1/Bub3 complex is recruited by TAp73 to the BCL2L1 promoter to mediate DNA methylation and repress transcription of this anti-apoptotic gene, promoting apoptosis. C-Src phosphorylates DMAP1 at Tyr246, which impedes DMAP1/Bub3 interaction and the resulting apoptotic activity, conferring mitotic stress resistance in pancreatic cancer cells. Co-immunoprecipitation, phospho-site mutagenesis, chromatin immunoprecipitation (ChIP), bisulfite sequencing, in vivo tumor models, kinase assay Molecular cancer High 30553276
2019 Loss of Dmap1 in a cardiac reprogramming system reduced promoter methylation, increased expression of Nkx2-5, and enhanced self-renewal while inhibiting further differentiation (due to sustained Cdh1 expression), establishing Dmap1 as a modulator of cardiac progenitor reprogramming through epigenetic (promoter methylation) control. CRISPR-Cas9 knockout screen, promoter methylation analysis, gene expression analysis, cell differentiation assays Stem cells Medium 30932271
2020 MMTR/Dmap1 binds promoters of differentiation commitment genes in mouse ESCs (established by ChIP). MMTR/Dmap1 controls gene expression alterations during differentiation by crosstalk with polycomb group (PcG) proteins; the complex controls histone mark bivalency and transcriptional poising of commitment genes. Chromatin immunoprecipitation (ChIP), gene expression analysis during ESC differentiation, interaction with PcG proteins Cells Medium 32403252
2026 DMAP1 deficiency causes replication fork retardance, disturbs genome stability, and induces endogenous DNA damage, thereby activating IFN signaling-mediated anti-tumor immune response in lung cancer cells. DMAP1 was identified as a critical regulator of lung cancer progression via CRISPR-based knockout screen. CRISPR-based knockout screen, replication fork assay, DNA damage assay, IFN signaling pathway analysis, immune cell assays Advanced science Medium 41904944
2025 DAXX interacts with DMAP1 to maintain DNA methylation of LINE1 elements in meiotic cells during spermatogenesis in mice. Conditional knockout of Daxx in germ cells leads to activation of young LINE1 and ERV subfamilies, and this is mechanistically linked to DAXX-DMAP1 interaction preserving DNA methylation at these loci. Conditional knockout (Ddx4-cre), co-immunoprecipitation (DAXX-DMAP1 interaction), DNA methylation analysis, transposable element expression analysis bioRxivpreprint Low bio_10.1101_2025.07.24.666258

Source papers

Stage 0 corpus · 20 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2000 DNMT1 binds HDAC2 and a new co-repressor, DMAP1, to form a complex at replication foci. Nature genetics 844 10888872
2004 Physical and functional interactions between Daxx and DNA methyltransferase 1-associated protein, DMAP1. Journal of immunology (Baltimore, Md. : 1950) 76 14978102
2010 DNA methyltransferase 1-associated protein (DMAP1) is a co-repressor that stimulates DNA methylation globally and locally at sites of double strand break repair. The Journal of biological chemistry 64 20864525
2015 MDGA2 is a novel tumour suppressor cooperating with DMAP1 in gastric cancer and is associated with disease outcome. Gut 63 26206665
2004 RGS6 interacts with DMAP1 and DNMT1 and inhibits DMAP1 transcriptional repressor activity. The Journal of biological chemistry 54 14734556
2011 Distinct roles of DMAP1 in mouse development. Molecular and cellular biology 32 21383065
2009 Dmap1 plays an essential role in the maintenance of genome integrity through the DNA repair process. Genes to cells : devoted to molecular & cellular mechanisms 30 19845771
2013 DMAP1 is an essential regulator of ATM activity and function. Oncogene 28 23318425
2020 ARID1A Regulates Transcription and the Epigenetic Landscape via POLE and DMAP1 while ARID1A Deficiency or Pharmacological Inhibition Sensitizes Germ Cell Tumor Cells to ATR Inhibition. Cancers 22 32272809
2014 The chromatin regulator DMAP1 modulates activity of the nuclear factor B (NF-B) transcription factor Relish in the Drosophila innate immune response. The Journal of biological chemistry 21 24947515
2019 CRISPR-Knockout Screen Identifies Dmap1 as a Regulator of Chemically Induced Reprogramming and Differentiation of Cardiac Progenitors. Stem cells (Dayton, Ohio) 15 30932271
2019 Silencing of the DNA methyltransferase 1 associated protein 1 (DMAP1) gene in the invasive ladybird Harmonia axyridis implies a role of the DNA methyltransferase 1-DMAP1 complex in female fecundity. Insect molecular biology 14 31531894
2018 C-Src confers resistance to mitotic stress through inhibition DMAP1/Bub3 complex formation in pancreatic cancer. Molecular cancer 12 30553276
2007 Corepressor MMTR/DMAP1 is involved in both histone deacetylase 1- and TFIIH-mediated transcriptional repression. Molecular and cellular biology 12 17371848
2020 MMTR/Dmap1 Sets the Stage for Early Lineage Commitment of Embryonic Stem Cells by Crosstalk with PcG Proteins. Cells 5 32403252
2010 Corepressor MMTR/DMAP1 is an intrinsic negative regulator of CAK kinase to regulate cell cycle progression. Biochemical and biophysical research communications 3 20920467
2024 The DNA methyltransferase DMAP1 is required for tissue maintenance and planarian regeneration. Developmental biology 2 39179016
2024 Identification, characterization, and CADD analysis of Plasmodium DMAP1 reveals it as a potential molecular target for new anti-malarial discovery. Journal of biomolecular structure & dynamics 1 38217317
2026 DMAP1 Deficiency Suppresses Lung Cancer Progression by Destabilizing Replication Fork and Activating IFN Signaling-Mediated Anti-tumor Immunity. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 0 41904944
2024 The DNA Methyltransferase DMAP1 is Required for Tissue Maintenance and Planarian Regeneration. bioRxiv : the preprint server for biology 0 38645093

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