{"gene":"DMAP1","run_date":"2026-06-09T23:54:42","timeline":{"discoveries":[{"year":2000,"finding":"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.","method":"Co-immunoprecipitation, yeast two-hybrid, transcription repression assays, immunofluorescence/colocalization at replication foci","journal":"Nature genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, transcriptional repression assays, direct localization experiments; foundational paper independently replicated by subsequent studies","pmids":["10888872"],"is_preprint":false},{"year":2004,"finding":"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.","method":"Yeast two-hybrid screen, co-immunoprecipitation, luciferase reporter transcription assay, immunofluorescence colocalization, protein stability assay","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP and functional transcription assay, single lab, multiple orthogonal methods","pmids":["14978102"],"is_preprint":false},{"year":2004,"finding":"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.","method":"Yeast two-hybrid screen, co-immunoprecipitation, deletion mutagenesis, GFP-localization, transcriptional repression assay","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP with domain mapping, multiple orthogonal methods, single lab","pmids":["14734556"],"is_preprint":false},{"year":2007,"finding":"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.","method":"Yeast two-hybrid, co-immunoprecipitation, in vitro kinase assay, luciferase reporter assay, dominant-negative HDAC1 competition","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro kinase assay with functional mutagenesis, reciprocal Co-IP, multiple orthogonal assays in single study","pmids":["17371848"],"is_preprint":false},{"year":2009,"finding":"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.","method":"shRNA knockdown, immunofluorescence/colocalization, co-immunoprecipitation, re-introduction of binding-deficient Dmap1 mutants, γ-H2AX foci assay","journal":"Genes to cells","confidence":"High","confidence_rationale":"Tier 2 / Moderate — loss-of-function with defined molecular phenotype, mutant rescue experiments, multiple orthogonal methods in single study","pmids":["19845771"],"is_preprint":false},{"year":2010,"finding":"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.","method":"In vitro DNA methylation assay, lentiviral shRNA knockdown, bisulfite sequencing, fluorescence-based HR reporter, chromatin immunoprecipitation (ChIP)","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro enzymatic assay plus multiple in vivo orthogonal methods (bisulfite sequencing, ChIP, HR reporter), single lab","pmids":["20864525"],"is_preprint":false},{"year":2010,"finding":"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.","method":"Overexpression, co-expression rescue, cell cycle analysis (flow cytometry), kinase assay","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — kinase assay with cell cycle phenotype readout, rescue by co-expression, single lab","pmids":["20920467"],"is_preprint":false},{"year":2011,"finding":"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.","method":"Genetic knockout (null allele generation), co-immunoprecipitation, bisulfite sequencing of imprinted genes, stable vs. transient expression comparison","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo genetic knockout with defined epigenetic phenotype, Co-IP, bisulfite sequencing; multiple orthogonal methods","pmids":["21383065"],"is_preprint":false},{"year":2013,"finding":"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.","method":"shRNA knockdown, overexpression, IR treatment, ATM substrate phosphorylation assay, G2/M checkpoint assay, H4K16 acetylation assay, HDAC inhibitor rescue, HAT activity assay","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 / Moderate — loss- and gain-of-function with defined molecular phenotype, epistasis via HDAC inhibitor rescue, multiple orthogonal methods in single study","pmids":["23318425"],"is_preprint":false},{"year":2014,"finding":"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.","method":"Co-immunoprecipitation, RNAi silencing in S2 cells and in vivo, antimicrobial peptide expression assay, epistasis analysis","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, in vivo RNAi, epistasis analysis; Drosophila ortholog study with multiple methods","pmids":["24947515"],"is_preprint":false},{"year":2018,"finding":"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.","method":"Co-immunoprecipitation, phospho-site mutagenesis, chromatin immunoprecipitation (ChIP), bisulfite sequencing, in vivo tumor models, kinase assay","journal":"Molecular cancer","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro kinase assay, ChIP, bisulfite sequencing, mutagenesis of phospho-sites, multiple orthogonal methods in single study","pmids":["30553276"],"is_preprint":false},{"year":2019,"finding":"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.","method":"CRISPR-Cas9 knockout screen, promoter methylation analysis, gene expression analysis, cell differentiation assays","journal":"Stem cells","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — CRISPR KO with defined epigenetic and differentiation phenotype, single lab, single study","pmids":["30932271"],"is_preprint":false},{"year":2020,"finding":"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.","method":"Chromatin immunoprecipitation (ChIP), gene expression analysis during ESC differentiation, interaction with PcG proteins","journal":"Cells","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — ChIP with functional gene expression readout, mechanistic model proposed with partial experimental support, single lab","pmids":["32403252"],"is_preprint":false},{"year":2026,"finding":"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.","method":"CRISPR-based knockout screen, replication fork assay, DNA damage assay, IFN signaling pathway analysis, immune cell assays","journal":"Advanced science","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — functional CRISPR KO with defined molecular phenotype (replication fork, IFN signaling), single lab, mechanistic details limited in abstract","pmids":["41904944"],"is_preprint":false},{"year":2025,"finding":"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.","method":"Conditional knockout (Ddx4-cre), co-immunoprecipitation (DAXX-DMAP1 interaction), DNA methylation analysis, transposable element expression analysis","journal":"bioRxiv","confidence":"Low","confidence_rationale":"Tier 3 / Weak — preprint, Co-IP for interaction, KO phenotype; mechanistic link between DAXX-DMAP1 interaction and LINE1 methylation inferred but not fully reconstituted","pmids":["bio_10.1101_2025.07.24.666258"],"is_preprint":true}],"current_model":"DMAP1 is a multifunctional chromatin-associated co-repressor that, through its N-terminal interaction with DNMT1, is constitutively targeted to replication foci throughout S phase where it directly stimulates DNMT1 methyltransferase activity and recruits HDAC2 during late S phase to establish repressive chromatin; it also functions as a component of the TIP60-p400 histone acetyltransferase complex where it is required for H4K16 acetylation and ATM activation upon DNA damage, recruits PCNA to DNA repair sites via direct binding, and is phosphorylated at Tyr246 by c-Src (blocking Bub3 complex formation) or acts with Bub3 (after p38-mediated Bub3-Ser211 phosphorylation) to repress anti-apoptotic gene BCL2L1 at sites of mitotic stress; additional interactions with TSG101, Daxx, RGS6, MAT1/CAK, HDAC1, PcG proteins, and Relish/Akirin/BAP55 further expand its roles in transcriptional repression, cell cycle regulation, and innate immune signaling."},"narrative":{"mechanistic_narrative":"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].","teleology":[{"year":2000,"claim":"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","pmids":["10888872"],"confidence":"High","gaps":["Structural basis of the DNMT1 N-terminus interaction not defined","Genomic targets of the complex not mapped at this stage"]},{"year":2004,"claim":"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","pmids":["14978102","14734556"],"confidence":"Medium","gaps":["Physiological contexts where Daxx/RGS6 control DMAP1 unclear","RGS6 GGL-domain interaction not structurally resolved"]},{"year":2007,"claim":"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","pmids":["17371848"],"confidence":"High","gaps":["Promoter contexts using the MAT1 versus HDAC route not delineated","In vivo significance of CTD inhibition not tested"]},{"year":2009,"claim":"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","pmids":["19845771"],"confidence":"High","gaps":["Which repair pathway PCNA stabilization serves not fully specified","Relationship to the DNMT1 versus TIP60 complex at damage sites unresolved"]},{"year":2010,"claim":"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","pmids":["20864525"],"confidence":"High","gaps":["Mechanism coupling methylation to HR suppression not defined","Whether enzymatic stimulation requires the full complex unknown"]},{"year":2010,"claim":"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","pmids":["20920467"],"confidence":"Medium","gaps":["Endogenous-level requirement for cell-cycle control not established","Overexpression artefact possibility not excluded"]},{"year":2011,"claim":"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","pmids":["21383065"],"confidence":"High","gaps":["Whether lethality reflects TIP60-p400 or DNMT1 function not separable","Tissue-specific roles not addressed by constitutive null"]},{"year":2013,"claim":"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","pmids":["23318425"],"confidence":"High","gaps":["Direct biochemical role of DMAP1 in HAT catalysis versus recruitment unclear","Link to its PCNA-stabilizing repair function not integrated"]},{"year":2014,"claim":"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","pmids":["24947515"],"confidence":"Medium","gaps":["Whether mammalian DMAP1 has an equivalent NF-kB role untested","Molecular step DMAP1 performs in the pathway undefined"]},{"year":2018,"claim":"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","pmids":["30553276"],"confidence":"High","gaps":["Generality beyond pancreatic cancer not tested","How TAp73 selects the BCL2L1 locus not detailed"]},{"year":2020,"claim":"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","pmids":["32403252"],"confidence":"Medium","gaps":["Direct biochemical PcG interaction not fully mapped","Causal contribution to bivalency versus correlation unresolved"]},{"year":2026,"claim":"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","pmids":["41904944"],"confidence":"Medium","gaps":["Mechanism connecting fork stress to IFN activation not detailed","Whether this reflects methylation or TIP60 function unclear"]},{"year":2025,"claim":"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)","pmids":["bio_10.1101_2025.07.24.666258"],"confidence":"Low","gaps":["Mechanistic link between DAXX-DMAP1 binding and LINE1 methylation inferred, not reconstituted","Preprint, not peer-reviewed","Direct DMAP1 requirement (versus DAXX alone) not isolated"]},{"year":null,"claim":"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.","evidence":"","pmids":[],"confidence":"Medium","gaps":["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":{"molecular_activity":[{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[0,2,3]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[5,6,8]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,4,8]},{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[5,12]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0,1]},{"term_id":"GO:0000228","term_label":"nuclear chromosome","supporting_discovery_ids":[0,4,5]}],"pathway":[{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[0,7,12]},{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[4,8]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[6,8,10]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[0,3]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[10]}],"complexes":["DNMT1-DMAP1-HDAC2 repressor complex","TIP60-p400 histone acetyltransferase complex"],"partners":["DNMT1","HDAC2","HDAC1","TSG101","DAXX","RGS6","MAT1","PCNA"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9NPF5","full_name":"DNA methyltransferase 1-associated protein 1","aliases":[],"length_aa":467,"mass_kda":53.0,"function":"Involved in transcription repression and activation. Its interaction with HDAC2 may provide a mechanism for histone deacetylation in heterochromatin following replication of DNA at late firing origins. Can also repress transcription independently of histone deacetylase activity. May specifically potentiate DAXX-mediated repression of glucocorticoid receptor-dependent transcription. Component of the NuA4 histone acetyltransferase (HAT) complex which is involved in transcriptional activation of select genes principally by acetylation of nucleosomal histones H4 and H2A. This modification may both alter nucleosome - DNA interactions and promote interaction of the modified histones with other proteins which positively regulate transcription. This complex may be required for the activation of transcriptional programs associated with oncogene and proto-oncogene mediated growth induction, tumor suppressor mediated growth arrest and replicative senescence, apoptosis, and DNA repair. NuA4 may also play a direct role in DNA repair when recruited to sites of DNA damage. Participates in the nuclear localization of URI1 and increases its transcriptional corepressor activity","subcellular_location":"Nucleus; Cytoplasm","url":"https://www.uniprot.org/uniprotkb/Q9NPF5/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/DMAP1","classification":"Common Essential","n_dependent_lines":1201,"n_total_lines":1208,"dependency_fraction":0.9942052980132451},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"ACTB","stoichiometry":0.2},{"gene":"CALM2","stoichiometry":0.2},{"gene":"CALM3","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/DMAP1","total_profiled":1310},"omim":[{"mim_id":"611379","title":"DISCO-INTERACTING PROTEIN 2 HOMOLOG B; DIP2B","url":"https://www.omim.org/entry/611379"},{"mim_id":"607840","title":"N-ACETYLGLUCOSAMINE-1-PHOSPHOTRANSFERASE, ALPHA/BETA SUBUNITS; GNPTAB","url":"https://www.omim.org/entry/607840"},{"mim_id":"605164","title":"HISTONE DEACETYLASE 2; HDAC2","url":"https://www.omim.org/entry/605164"},{"mim_id":"605077","title":"DNA METHYLTRANSFERASE 1-ASSOCIATED PROTEIN 1; DMAP1","url":"https://www.omim.org/entry/605077"},{"mim_id":"603186","title":"DEATH-ASSOCIATED PROTEIN 6; DAXX","url":"https://www.omim.org/entry/603186"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/DMAP1"},"hgnc":{"alias_symbol":["DNMAP1","FLJ11543","KIAA1425","DNMTAP1","EAF2","MEAF2","SWC4"],"prev_symbol":[]},"alphafold":{"accession":"Q9NPF5","domains":[{"cath_id":"-","chopping":"94-128","consensus_level":"medium","plddt":87.0194,"start":94,"end":128},{"cath_id":"1.10.10.60","chopping":"139-234","consensus_level":"medium","plddt":93.6412,"start":139,"end":234},{"cath_id":"-","chopping":"322-396","consensus_level":"high","plddt":90.1721,"start":322,"end":396}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9NPF5","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9NPF5-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9NPF5-F1-predicted_aligned_error_v6.png","plddt_mean":73.75},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=DMAP1","jax_strain_url":"https://www.jax.org/strain/search?query=DMAP1"},"sequence":{"accession":"Q9NPF5","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9NPF5.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9NPF5/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9NPF5"}},"corpus_meta":[{"pmid":"10888872","id":"PMC_10888872","title":"DNMT1 binds HDAC2 and a new co-repressor, DMAP1, to form a complex at replication foci.","date":"2000","source":"Nature genetics","url":"https://pubmed.ncbi.nlm.nih.gov/10888872","citation_count":844,"is_preprint":false},{"pmid":"14978102","id":"PMC_14978102","title":"Physical and functional interactions between Daxx and DNA methyltransferase 1-associated protein, DMAP1.","date":"2004","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/14978102","citation_count":76,"is_preprint":false},{"pmid":"20864525","id":"PMC_20864525","title":"DNA methyltransferase 1-associated protein (DMAP1) is a co-repressor that stimulates DNA methylation globally and locally at sites of double strand break repair.","date":"2010","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/20864525","citation_count":64,"is_preprint":false},{"pmid":"26206665","id":"PMC_26206665","title":"MDGA2 is a novel tumour suppressor cooperating with DMAP1 in gastric cancer and is associated with disease outcome.","date":"2015","source":"Gut","url":"https://pubmed.ncbi.nlm.nih.gov/26206665","citation_count":63,"is_preprint":false},{"pmid":"14734556","id":"PMC_14734556","title":"RGS6 interacts with DMAP1 and DNMT1 and inhibits DMAP1 transcriptional repressor activity.","date":"2004","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/14734556","citation_count":54,"is_preprint":false},{"pmid":"21383065","id":"PMC_21383065","title":"Distinct roles of DMAP1 in mouse development.","date":"2011","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/21383065","citation_count":32,"is_preprint":false},{"pmid":"19845771","id":"PMC_19845771","title":"Dmap1 plays an essential role in the maintenance of genome integrity through the DNA repair process.","date":"2009","source":"Genes to cells : devoted to molecular & cellular 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chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/24947515","citation_count":21,"is_preprint":false},{"pmid":"30932271","id":"PMC_30932271","title":"CRISPR-Knockout Screen Identifies Dmap1 as a Regulator of Chemically Induced Reprogramming and Differentiation of Cardiac Progenitors.","date":"2019","source":"Stem cells (Dayton, Ohio)","url":"https://pubmed.ncbi.nlm.nih.gov/30932271","citation_count":15,"is_preprint":false},{"pmid":"31531894","id":"PMC_31531894","title":"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.","date":"2019","source":"Insect molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/31531894","citation_count":14,"is_preprint":false},{"pmid":"30553276","id":"PMC_30553276","title":"C-Src confers resistance to mitotic stress through inhibition DMAP1/Bub3 complex formation in pancreatic cancer.","date":"2018","source":"Molecular cancer","url":"https://pubmed.ncbi.nlm.nih.gov/30553276","citation_count":12,"is_preprint":false},{"pmid":"17371848","id":"PMC_17371848","title":"Corepressor MMTR/DMAP1 is involved in both histone deacetylase 1- and TFIIH-mediated transcriptional repression.","date":"2007","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/17371848","citation_count":12,"is_preprint":false},{"pmid":"32403252","id":"PMC_32403252","title":"MMTR/Dmap1 Sets the Stage for Early Lineage Commitment of Embryonic Stem Cells by Crosstalk with PcG Proteins.","date":"2020","source":"Cells","url":"https://pubmed.ncbi.nlm.nih.gov/32403252","citation_count":5,"is_preprint":false},{"pmid":"20920467","id":"PMC_20920467","title":"Corepressor MMTR/DMAP1 is an intrinsic negative regulator of CAK kinase to regulate cell cycle progression.","date":"2010","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/20920467","citation_count":3,"is_preprint":false},{"pmid":"39179016","id":"PMC_39179016","title":"The DNA methyltransferase DMAP1 is required for tissue maintenance and planarian regeneration.","date":"2024","source":"Developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/39179016","citation_count":2,"is_preprint":false},{"pmid":"38217317","id":"PMC_38217317","title":"Identification, characterization, and CADD analysis of Plasmodium DMAP1 reveals it as a potential molecular target for new anti-malarial discovery.","date":"2024","source":"Journal of biomolecular structure & dynamics","url":"https://pubmed.ncbi.nlm.nih.gov/38217317","citation_count":1,"is_preprint":false},{"pmid":"38645093","id":"PMC_38645093","title":"The DNA Methyltransferase DMAP1 is Required for Tissue Maintenance and Planarian Regeneration.","date":"2024","source":"bioRxiv : the preprint server for biology","url":"https://pubmed.ncbi.nlm.nih.gov/38645093","citation_count":0,"is_preprint":false},{"pmid":"41904944","id":"PMC_41904944","title":"DMAP1 Deficiency Suppresses Lung Cancer Progression by Destabilizing Replication Fork and Activating IFN Signaling-Mediated Anti-tumor Immunity.","date":"2026","source":"Advanced science (Weinheim, Baden-Wurttemberg, Germany)","url":"https://pubmed.ncbi.nlm.nih.gov/41904944","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.07.24.666258","title":"DAXX governs the silencing of LINE1 during spermatogenesis in mice","date":"2025-07-29","source":"bioRxiv","url":"https://doi.org/10.1101/2025.07.24.666258","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":12216,"output_tokens":4310,"usd":0.050649,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":12241,"output_tokens":4549,"usd":0.087465,"stage2_stop_reason":"end_turn"},"total_usd":0.138114,"stage1_batch_id":"msgbatch_01AsR7g8dGTEiEw9U83bJeWn","stage2_batch_id":"msgbatch_01YV5ZyxtFNUZEjxRcpd9jzb","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2000,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation, yeast two-hybrid, transcription repression assays, immunofluorescence/colocalization at replication foci\",\n      \"journal\": \"Nature genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, transcriptional repression assays, direct localization experiments; foundational paper independently replicated by subsequent studies\",\n      \"pmids\": [\"10888872\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"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.\",\n      \"method\": \"Yeast two-hybrid screen, co-immunoprecipitation, luciferase reporter transcription assay, immunofluorescence colocalization, protein stability assay\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP and functional transcription assay, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"14978102\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"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.\",\n      \"method\": \"Yeast two-hybrid screen, co-immunoprecipitation, deletion mutagenesis, GFP-localization, transcriptional repression assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP with domain mapping, multiple orthogonal methods, single lab\",\n      \"pmids\": [\"14734556\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"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.\",\n      \"method\": \"Yeast two-hybrid, co-immunoprecipitation, in vitro kinase assay, luciferase reporter assay, dominant-negative HDAC1 competition\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro kinase assay with functional mutagenesis, reciprocal Co-IP, multiple orthogonal assays in single study\",\n      \"pmids\": [\"17371848\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"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.\",\n      \"method\": \"shRNA knockdown, immunofluorescence/colocalization, co-immunoprecipitation, re-introduction of binding-deficient Dmap1 mutants, γ-H2AX foci assay\",\n      \"journal\": \"Genes to cells\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function with defined molecular phenotype, mutant rescue experiments, multiple orthogonal methods in single study\",\n      \"pmids\": [\"19845771\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"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.\",\n      \"method\": \"In vitro DNA methylation assay, lentiviral shRNA knockdown, bisulfite sequencing, fluorescence-based HR reporter, chromatin immunoprecipitation (ChIP)\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro enzymatic assay plus multiple in vivo orthogonal methods (bisulfite sequencing, ChIP, HR reporter), single lab\",\n      \"pmids\": [\"20864525\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"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.\",\n      \"method\": \"Overexpression, co-expression rescue, cell cycle analysis (flow cytometry), kinase assay\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — kinase assay with cell cycle phenotype readout, rescue by co-expression, single lab\",\n      \"pmids\": [\"20920467\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"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.\",\n      \"method\": \"Genetic knockout (null allele generation), co-immunoprecipitation, bisulfite sequencing of imprinted genes, stable vs. transient expression comparison\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo genetic knockout with defined epigenetic phenotype, Co-IP, bisulfite sequencing; multiple orthogonal methods\",\n      \"pmids\": [\"21383065\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"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.\",\n      \"method\": \"shRNA knockdown, overexpression, IR treatment, ATM substrate phosphorylation assay, G2/M checkpoint assay, H4K16 acetylation assay, HDAC inhibitor rescue, HAT activity assay\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss- and gain-of-function with defined molecular phenotype, epistasis via HDAC inhibitor rescue, multiple orthogonal methods in single study\",\n      \"pmids\": [\"23318425\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation, RNAi silencing in S2 cells and in vivo, antimicrobial peptide expression assay, epistasis analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, in vivo RNAi, epistasis analysis; Drosophila ortholog study with multiple methods\",\n      \"pmids\": [\"24947515\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation, phospho-site mutagenesis, chromatin immunoprecipitation (ChIP), bisulfite sequencing, in vivo tumor models, kinase assay\",\n      \"journal\": \"Molecular cancer\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro kinase assay, ChIP, bisulfite sequencing, mutagenesis of phospho-sites, multiple orthogonal methods in single study\",\n      \"pmids\": [\"30553276\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"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.\",\n      \"method\": \"CRISPR-Cas9 knockout screen, promoter methylation analysis, gene expression analysis, cell differentiation assays\",\n      \"journal\": \"Stem cells\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — CRISPR KO with defined epigenetic and differentiation phenotype, single lab, single study\",\n      \"pmids\": [\"30932271\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"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.\",\n      \"method\": \"Chromatin immunoprecipitation (ChIP), gene expression analysis during ESC differentiation, interaction with PcG proteins\",\n      \"journal\": \"Cells\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — ChIP with functional gene expression readout, mechanistic model proposed with partial experimental support, single lab\",\n      \"pmids\": [\"32403252\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"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.\",\n      \"method\": \"CRISPR-based knockout screen, replication fork assay, DNA damage assay, IFN signaling pathway analysis, immune cell assays\",\n      \"journal\": \"Advanced science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — functional CRISPR KO with defined molecular phenotype (replication fork, IFN signaling), single lab, mechanistic details limited in abstract\",\n      \"pmids\": [\"41904944\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"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.\",\n      \"method\": \"Conditional knockout (Ddx4-cre), co-immunoprecipitation (DAXX-DMAP1 interaction), DNA methylation analysis, transposable element expression analysis\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — preprint, Co-IP for interaction, KO phenotype; mechanistic link between DAXX-DMAP1 interaction and LINE1 methylation inferred but not fully reconstituted\",\n      \"pmids\": [\"bio_10.1101_2025.07.24.666258\"],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"DMAP1 is a multifunctional chromatin-associated co-repressor that, through its N-terminal interaction with DNMT1, is constitutively targeted to replication foci throughout S phase where it directly stimulates DNMT1 methyltransferase activity and recruits HDAC2 during late S phase to establish repressive chromatin; it also functions as a component of the TIP60-p400 histone acetyltransferase complex where it is required for H4K16 acetylation and ATM activation upon DNA damage, recruits PCNA to DNA repair sites via direct binding, and is phosphorylated at Tyr246 by c-Src (blocking Bub3 complex formation) or acts with Bub3 (after p38-mediated Bub3-Ser211 phosphorylation) to repress anti-apoptotic gene BCL2L1 at sites of mitotic stress; additional interactions with TSG101, Daxx, RGS6, MAT1/CAK, HDAC1, PcG proteins, and Relish/Akirin/BAP55 further expand its roles in transcriptional repression, cell cycle regulation, and innate immune signaling.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"DMAP1 is a chromatin-associated co-repressor that couples DNA methylation to histone modification and DNA-damage signaling across S phase and beyond [#0, #5]. 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 [#0]; 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 [#0, #5, #7]. Genetic loss of DMAP1 is lethal at preimplantation and abolishes maintenance methylation, consistent with its dual membership in the DNMT1 and TIP60-p400 complexes [#7]. 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 [#8]; it is independently recruited to damage sites where it binds and stabilizes PCNA to enable efficient repair and restrain hyper-recombination [#4, #5]. 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 [#3, #6]. 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 [#10]. In embryonic stem cells DMAP1 occupies differentiation-commitment gene promoters and cooperates with Polycomb proteins to set histone bivalency [#12].\",\n  \"teleology\": [\n    {\n      \"year\": 2000,\n      \"claim\": \"Established DMAP1's founding identity: how is DNMT1-associated transcriptional repression organized, and what links DNA methylation machinery to histone deacetylation across S phase?\",\n      \"evidence\": \"Co-IP, yeast two-hybrid, transcription repression assays, and colocalization at replication foci\",\n      \"pmids\": [\"10888872\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of the DNMT1 N-terminus interaction not defined\", \"Genomic targets of the complex not mapped at this stage\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"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.\",\n      \"evidence\": \"Yeast two-hybrid, reciprocal Co-IP, luciferase reporter assays, and protein-stability assays\",\n      \"pmids\": [\"14978102\", \"14734556\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Physiological contexts where Daxx/RGS6 control DMAP1 unclear\", \"RGS6 GGL-domain interaction not structurally resolved\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"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.\",\n      \"evidence\": \"Yeast two-hybrid, Co-IP, in vitro kinase assay, and dominant-negative HDAC1 competition\",\n      \"pmids\": [\"17371848\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Promoter contexts using the MAT1 versus HDAC route not delineated\", \"In vivo significance of CTD inhibition not tested\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"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.\",\n      \"evidence\": \"shRNA knockdown, immunofluorescence, Co-IP, and binding-deficient mutant rescue\",\n      \"pmids\": [\"19845771\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Which repair pathway PCNA stabilization serves not fully specified\", \"Relationship to the DNMT1 versus TIP60 complex at damage sites unresolved\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Demonstrated DMAP1 directly activates DNMT1 enzymatic activity and links methylation to recombination, methylating both p16 and HR repair products and restraining HR.\",\n      \"evidence\": \"In vitro methylation assay, shRNA, bisulfite sequencing, HR reporter, and ChIP\",\n      \"pmids\": [\"20864525\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism coupling methylation to HR suppression not defined\", \"Whether enzymatic stimulation requires the full complex unknown\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Connected DMAP1 to cell-cycle timing: overexpression delays G1/S and G2/M via MAT1-dependent inhibition of CAK-mediated CDK1 phosphorylation.\",\n      \"evidence\": \"Overexpression, co-expression rescue, flow cytometry, and kinase assay\",\n      \"pmids\": [\"20920467\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Endogenous-level requirement for cell-cycle control not established\", \"Overexpression artefact possibility not excluded\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"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.\",\n      \"evidence\": \"Genetic null allele, Co-IP, and bisulfite sequencing of imprinted genes\",\n      \"pmids\": [\"21383065\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether lethality reflects TIP60-p400 or DNMT1 function not separable\", \"Tissue-specific roles not addressed by constitutive null\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"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.\",\n      \"evidence\": \"shRNA, overexpression, ATM substrate phosphorylation, H4K16ac, HAT activity, and HDAC-inhibitor rescue\",\n      \"pmids\": [\"23318425\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct biochemical role of DMAP1 in HAT catalysis versus recruitment unclear\", \"Link to its PCNA-stabilizing repair function not integrated\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"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.\",\n      \"evidence\": \"Co-IP, RNAi in S2 cells and in vivo, and epistasis analysis\",\n      \"pmids\": [\"24947515\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether mammalian DMAP1 has an equivalent NF-kB role untested\", \"Molecular step DMAP1 performs in the pathway undefined\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"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.\",\n      \"evidence\": \"Co-IP, phospho-site mutagenesis, ChIP, bisulfite sequencing, kinase assays, and in vivo tumor models\",\n      \"pmids\": [\"30553276\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Generality beyond pancreatic cancer not tested\", \"How TAp73 selects the BCL2L1 locus not detailed\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Showed DMAP1 shapes stem-cell fate by occupying differentiation-commitment promoters and cooperating with Polycomb proteins to set histone bivalency and poising.\",\n      \"evidence\": \"ChIP and gene-expression analysis during ESC differentiation with PcG interaction data\",\n      \"pmids\": [\"32403252\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct biochemical PcG interaction not fully mapped\", \"Causal contribution to bivalency versus correlation unresolved\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"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.\",\n      \"evidence\": \"CRISPR knockout screen, replication fork and DNA damage assays, IFN pathway and immune-cell analyses\",\n      \"pmids\": [\"41904944\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism connecting fork stress to IFN activation not detailed\", \"Whether this reflects methylation or TIP60 function unclear\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Implicated DMAP1 in transposon silencing during spermatogenesis: DAXX-DMAP1 interaction maintains LINE1/ERV DNA methylation in meiotic germ cells.\",\n      \"evidence\": \"Conditional Daxx knockout, Co-IP, and DNA methylation and transposon expression analysis (preprint)\",\n      \"pmids\": [\"bio_10.1101_2025.07.24.666258\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Mechanistic link between DAXX-DMAP1 binding and LINE1 methylation inferred, not reconstituted\", \"Preprint, not peer-reviewed\", \"Direct DMAP1 requirement (versus DAXX alone) not isolated\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"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.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"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\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [0, 2, 3]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [5, 6, 8]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 4, 8]},\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [5, 12]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"GO:0000228\", \"supporting_discovery_ids\": [0, 4, 5]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [0, 7, 12]},\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [4, 8]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [6, 8, 10]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [0, 3]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [10]}\n    ],\n    \"complexes\": [\n      \"DNMT1-DMAP1-HDAC2 repressor complex\",\n      \"TIP60-p400 histone acetyltransferase complex\"\n    ],\n    \"partners\": [\n      \"DNMT1\",\n      \"HDAC2\",\n      \"HDAC1\",\n      \"TSG101\",\n      \"Daxx\",\n      \"RGS6\",\n      \"MAT1\",\n      \"PCNA\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}