Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0003886 DNA (cytosine-5-)-methyltransferase activity	IBA GO_REF:0000033	ACCEPT	Summary: This IBA annotation correctly identifies DNMT1 as having DNA (cytosine-5)-methyltransferase activity. This is the core catalytic function of DNMT1, well-established through extensive biochemical studies showing it methylates cytosine at the 5-position using S-adenosyl-L-methionine as methyl donor, with preference for hemimethylated CpG sites. Reason: This represents the primary and most fundamental molecular function of DNMT1. Multiple studies confirm DNMT1 catalyzes the methylation of cytosine residues at CpG sites, particularly hemimethylated sites during DNA replication maintenance. The IBA evidence represents phylogenetic analysis supporting this core function. Supporting Evidence: PMID:21745816 USP7 stimulated both the maintenance and de novo DNA methylation activity of Dnmt1 in vitro PMID:18754681 CXXC domain of human DNMT1 is essential for enzymatic activity file:human/DNMT1/DNMT1-deep-research.md See deep research file for comprehensive analysis
GO:0005634 nucleus	IBA GO_REF:0000033	ACCEPT	Summary: DNMT1 is primarily nuclear localized, where it carries out DNA methylation during replication and associates with heterochromatin. Multiple studies confirm nuclear localization with specific enrichment at replication foci during S-phase and pericentric heterochromatin. Reason: Nuclear localization is well-established for DNMT1. The protein functions in the nucleus where DNA replication and chromatin organization occur. IBA phylogenetic evidence supports this conserved cellular compartmentalization across species. Supporting Evidence: PMID:8940105 DNA (cytosine-5)-methyltransferases (EC 2.1.1.37) maintain patterns of methylated cytosine residues in the mammalian genome PMID:16791210 Dynamic proteomics in individual human cells uncovers widespread cell-cycle dependence of nuclear proteins
GO:0044027 negative regulation of gene expression via chromosomal CpG island methylation	IBA GO_REF:0000033	ACCEPT	Summary: DNMT1 negatively regulates gene expression through CpG island methylation, leading to transcriptional silencing. This is a core biological process function of DNMT1, particularly important in cancer where hypermethylation silences tumor suppressor genes and in normal development for silencing tissue-inappropriate genes. Reason: This accurately describes a key biological process mediated by DNMT1. CpG island methylation by DNMT1 leads to transcriptional repression through recruitment of methyl-CpG binding proteins and chromatin remodeling complexes. Well-supported by literature showing DNMT1 role in silencing genes via promoter hypermethylation. Supporting Evidence: PMID:24623306 ZNF304 recruits a corepressor complex that includes the DNA methyltransferase DNMT1, resulting in DNA hypermethylation and transcriptional silencing PMID:21745816 Dnmt1, UHRF1 and USP7 co-localized on silenced, methylated genes in vivo
GO:0003677 DNA binding	IBA GO_REF:0000033	KEEP AS NON CORE	Summary: DNMT1 binds DNA through multiple domains including the CXXC domain (recognizes unmethylated CpG), catalytic domain (substrate binding), and other regions that interact with chromatin. While DNA binding is necessary for function, this term is quite general and less informative than the specific methyltransferase activity term. Reason: DNA binding is a prerequisite molecular function for DNMT1 to carry out its methyltransferase activity, but it is a general term that does not capture the specific enzymatic function. The more specific GO:0003886 (DNA cytosine-5-methyltransferase activity) is preferred as the core function. This term represents necessary but non-specific binding activity. Supporting Evidence: PMID:18754681 CXXC domain of human DNMT1 is essential for enzymatic activity
GO:0003677 DNA binding	IEA GO_REF:0000120	KEEP AS NON CORE	Summary: DNA binding annotation for DNMT1. Reason: DNA binding is accurate but less specific than the DNA methyltransferase activity annotation. Marked as non-core to avoid redundancy with more specific terms.
GO:0003682 chromatin binding	IEA GO_REF:0000120	ACCEPT	Summary: DNMT1 does bind chromatin through interactions with nucleosomes, histones, and chromatin proteins. It associates with heterochromatin and replication foci. However, this is a somewhat general term that could be made more specific. Reason: DNMT1 binding to chromatin is well-documented, including association with nucleosomes, modified histones, and heterochromatin. While general, chromatin binding is a legitimate molecular function distinct from DNA binding alone, as it involves the nucleoprotein complex rather than naked DNA. Supporting Evidence: PMID:21745816 UHRF1 strongly associates with heterochromatin (15,16) and binds preferentially to hemi-methylated DNA via its SRA domain (13,17–19)
GO:0003886 DNA (cytosine-5-)-methyltransferase activity	IEA GO_REF:0000120	ACCEPT	Summary: DNA (cytosine-5-)-methyltransferase activity annotation for DNMT1. Reason: DNA (cytosine-5-)-methyltransferase activity is the core catalytic function of DNMT1. Multiple evidence codes support this annotation.
GO:0005634 nucleus	IEA GO_REF:0000120	ACCEPT	Summary: nucleus annotation for DNMT1. Reason: Nuclear localization is essential for DNMT1's function in DNA methylation. Multiple evidence codes support this annotation.
GO:0006346 DNA methylation-dependent constitutive heterochromatin formation	IEA GO_REF:0000120	ACCEPT	Summary: DNMT1 contributes to heterochromatin formation through DNA methylation, particularly at repetitive elements and pericentromeric regions. This is a specific and accurate biological process annotation describing an important function of DNMT1 in chromatin organization. Reason: DNMT1 plays a well-documented role in heterochromatin formation through DNA methylation. This is particularly important at repetitive sequences, satellite DNA, and pericentromeric regions where DNMT1-mediated methylation helps establish and maintain heterochromatic states essential for genomic stability. Supporting Evidence: PMID:21745816 UHRF1 strongly associates with heterochromatin
GO:0008168 methyltransferase activity	IEA GO_REF:0000120	MODIFY	Summary: This is a broad parent term of the more specific DNA (cytosine-5-)-methyltransferase activity. While accurate, it is less informative than the specific terms already annotated. Reason: This general methyltransferase activity term is too broad. DNMT1 specifically catalyzes DNA cytosine-5-methylation, not general methylation. The more specific GO:0003886 (DNA cytosine-5-methyltransferase activity) is already annotated and preferred. Proposed replacements: DNA (cytosine-5-)-methyltransferase activity
GO:0008270 zinc ion binding	IEA GO_REF:0000120	ACCEPT	Summary: DNMT1 contains a CXXC zinc finger domain that coordinates zinc ions for proper folding and DNA binding function. This molecular function is structurally important for DNMT1 activity. Reason: The CXXC domain of DNMT1 is a zinc finger domain that requires zinc coordination for proper folding and function. This zinc finger domain recognizes unmethylated CpG sites and is essential for targeting DNMT1 to appropriate substrates. Zinc binding is a legitimate and important molecular function. Supporting Evidence: PMID:18754681 CXXC domain of human DNMT1 is essential for enzymatic activity
GO:0006325 chromatin organization	IEA GO_REF:0000043	ACCEPT	Summary: DNMT1 contributes to chromatin organization through DNA methylation-mediated recruitment of chromatin remodeling complexes and establishment of heterochromatin. This is a legitimate but broad biological process. Reason: DNMT1 plays important roles in chromatin organization by establishing methylation patterns that recruit methyl-CpG binding proteins, chromatin remodeling complexes, and help organize heterochromatin. While broad, this accurately describes an important biological process function of DNMT1. Supporting Evidence: PMID:21745816 UHRF1 strongly associates with heterochromatin
GO:0016740 transferase activity	IEA GO_REF:0000043	MODIFY	Summary: This is an extremely broad parent term for any enzyme that transfers functional groups. While technically correct since DNMT1 transfers methyl groups, it provides no specific information about DNMT1 function. Reason: This term is far too general and uninformative. DNMT1 specifically transfers methyl groups to DNA cytosines, which is already captured by the more specific GO:0003886 (DNA cytosine-5-methyltransferase activity). The broad transferase activity term should be replaced with the specific methyltransferase activity. Proposed replacements: DNA (cytosine-5-)-methyltransferase activity
GO:0032259 methylation	IEA GO_REF:0000043	MODIFY	Summary: This is a very general biological process term for any methylation reaction. While DNMT1 does perform methylation, more specific terms like DNA methylation-related processes are preferred. Reason: This general methylation term is too broad and uninformative. DNMT1 performs DNA methylation specifically, which is better captured by more specific terms like GO:0141119 (chromosomal DNA methylation maintenance) or GO:0044027 (negative regulation of gene expression via chromosomal CpG island methylation). Proposed replacements: chromosomal DNA methylation maintenance following DNA replication
GO:0046872 metal ion binding	IEA GO_REF:0000043	MODIFY	Summary: DNMT1 binds metal ions, particularly zinc in the CXXC domain. However, this is a broad term - the more specific zinc ion binding (GO:0008270) is already annotated and preferred. Reason: While DNMT1 does bind metal ions (zinc), this general term is less informative than the specific GO:0008270 (zinc ion binding) that is already annotated. The specific term is preferred over the general parent term. Proposed replacements: zinc ion binding
GO:0005515 protein binding	IPI PMID:15161933 Comprehensive proteomic analysis of interphase and mitotic 1...	MARK AS OVER ANNOTATED	Summary: DNMT1 extensively interacts with numerous proteins including UHRF1, PCNA, USP7, histones, and chromatin factors. However, protein binding is a very general term that does not specify the functional significance of these interactions. Reason: While DNMT1 does bind many proteins, this general protein binding term is not informative about DNMT1 specific functions. The numerous IPI annotations with this term represent over-annotation. More specific terms like chromatin binding or enzyme regulator activity would be more informative than generic protein binding. Supporting Evidence: PMID:15161933 2004 May 25. Comprehensive proteomic analysis of interphase and mitotic 14-3-3-binding proteins. PMID:17673620 Aug 2. UHRF1 plays a role in maintaining DNA methylation in mammalian cells. PMID:19450230 SUMOylation enhances DNA methyltransferase 1 activity. PMID:21745816 Jul 10. The USP7/Dnmt1 complex stimulates the DNA methylation activity of Dnmt1 and regulates the stability of UHRF1.
GO:0005515 protein binding	IPI PMID:16357870 The Polycomb group protein EZH2 directly controls DNA methyl...	MARK AS OVER ANNOTATED	Summary: Duplicate generic protein binding annotation - shows interaction with EZH2. Multiple IPI annotations exist for the same uninformative term. Reason: This represents over-annotation with the same general protein binding term. While this PMID demonstrates DNMT1-EZH2 interaction, the generic GO:0005515 protein binding term provides no functional specificity about this interaction. More specific terms would be more informative. Supporting Evidence: PMID:16357870 The Polycomb group protein EZH2 directly controls DNA methylation.
GO:0005515 protein binding	IPI PMID:16983096 Recruitment of the de novo DNA methyltransferase Dnmt3a by K...	MARK AS OVER ANNOTATED	Summary: Duplicate generic protein binding annotation. Over-annotation with uninformative term despite showing DNMT3A interaction. Reason: Generic protein binding term that does not capture functional significance of DNMT1-DNMT3A interaction. Represents over-annotation where multiple PMIDs are annotated to the same uninformative molecular function term. Supporting Evidence: PMID:16983096 Recruitment of the de novo DNA methyltransferase Dnmt3a by Kaposi's sarcoma-associated herpesvirus LANA.
GO:0005515 protein binding	IPI PMID:17934516 The interaction of the SRA domain of ICBP90 with a novel dom...	MARK AS OVER ANNOTATED	Summary: Another duplicate generic protein binding annotation showing DNMT1-ICBP90 interaction. Multiple IPI annotations with this uninformative term represent over-annotation. Reason: Generic protein binding term provides no functional specificity about the DNMT1-ICBP90/UHRF1 interaction. While this interaction is functionally important for DNMT1 targeting to hemimethylated sites, the generic GO:0005515 term is uninformative. More specific terms would better capture this regulatory interaction. Supporting Evidence: PMID:17934516 The interaction of the SRA domain of ICBP90 with a novel domain of DNMT1 is involved in the regulation of VEGF gene expression
GO:0005515 protein binding	IPI PMID:17972916 RIP140 directs histone and DNA methylation to silence Ucp1 e...	MARK AS OVER ANNOTATED	Summary: Generic protein binding annotation showing DNMT1-RIP140 interaction in adipocyte gene silencing context. Multiple uninformative protein binding annotations represent over-annotation. Reason: The generic protein binding term does not capture the functional significance of DNMT1-RIP140 interaction in transcriptional silencing of UCP1. While this interaction is functionally relevant, the GO:0005515 term provides no specificity about the regulatory nature of this interaction. Supporting Evidence: PMID:17972916 Nov 1. RIP140 directs histone and DNA methylation to silence Ucp1 expression in white adipocytes.
GO:0005515 protein binding	IPI PMID:19282482 Regulation of DNMT1 stability through SET7-mediated lysine m...	MARK AS OVER ANNOTATED	Summary: Generic protein binding annotation showing DNMT1-SET7 interaction involved in DNMT1 stability regulation via lysine methylation. Another uninformative generic annotation. Reason: The generic protein binding term fails to capture the regulatory significance of SET7-mediated DNMT1 methylation and stability control. While this represents an important post-translational modification pathway, the GO:0005515 term is too general to be informative. Supporting Evidence: PMID:19282482 Regulation of DNMT1 stability through SET7-mediated lysine methylation in mammalian cells
GO:0005515 protein binding	IPI PMID:19798101 Np95 interacts with de novo DNA methyltransferases, Dnmt3a a...	MARK AS OVER ANNOTATED	Summary: Generic protein binding annotation showing DNMT1-Np95/UHRF1 interaction mediating DNA methylation and gene silencing. Another example of uninformative generic annotation. Reason: While the DNMT1-UHRF1 interaction is crucial for maintenance methylation targeting, the generic protein binding term provides no functional information. This interaction involves chromatin targeting and enzyme regulation, which would be better captured by more specific molecular function terms. Supporting Evidence: PMID:19798101 Np95 interacts with de novo DNA methyltransferases, Dnmt3a and Dnmt3b, and mediates epigenetic silencing of the viral CMV promoter in embryonic stem cells
GO:0005515 protein binding	IPI PMID:21151116 A methylation and phosphorylation switch between an adjacent...	MARK AS OVER ANNOTATED	Summary: Generic protein binding annotation related to DNMT1 post-translational modifications affecting stability. The study shows methylation and phosphorylation switch regulating DNMT1. Reason: Generic protein binding term does not capture the regulatory significance of post-translational modifications controlling DNMT1 stability. The study focuses on regulatory modifications rather than specific protein-protein interactions, making this annotation uninformative. Supporting Evidence: PMID:21151116 A methylation and phosphorylation switch between an adjacent lysine and serine determines human DNMT1 stability
GO:0005515 protein binding	IPI PMID:21653829 Protein interactome reveals converging molecular pathways am...	MARK AS OVER ANNOTATED	Summary: Generic protein binding annotation from autism disorder protein interactome study. While DNMT1 may have interactions identified in this proteomics study, this represents uninformative over-annotation. Reason: This generic protein binding annotation from a broad proteomics study of autism-related proteins does not provide specific functional information about DNMT1. The connection to autism disorders is indirect and the generic GO term is uninformative about DNMT1 core functions. Supporting Evidence: PMID:21653829 Protein interactome reveals converging molecular pathways among autism disorders
GO:0005515 protein binding	IPI PMID:21947282 SIRT1 deacetylates the DNA methyltransferase 1 (DNMT1) prote...	MARK AS OVER ANNOTATED	Summary: Generic protein binding annotation showing DNMT1-SIRT1 interaction where SIRT1 deacetylates DNMT1 and alters its activity. Another uninformative generic annotation. Reason: While SIRT1 deacetylation of DNMT1 is functionally important for enzyme regulation, the generic protein binding term provides no specificity about this regulatory post-translational modification. More specific terms relating to enzyme regulation would be more informative. Supporting Evidence: PMID:21947282 SIRT1 deacetylates the DNA methyltransferase 1 (DNMT1) protein and alters its activities
GO:0005515 protein binding	IPI PMID:22094255 Oxidative damage targets complexes containing DNA methyltran...	MARK AS OVER ANNOTATED	Summary: Generic protein binding annotation from study of oxidative damage effects on DNMT1 complexes at CpG islands. Another uninformative generic annotation despite showing important regulatory context. Reason: While this study shows important effects of oxidative damage on DNMT1-containing complexes at promoters, the generic protein binding term does not capture the functional significance of these interactions or the regulatory context. Supporting Evidence: PMID:22094255 Oxidative damage targets complexes containing DNA methyltransferases, SIRT1, and polycomb members to promoter CpG Islands
GO:0005515 protein binding	IPI PMID:25544563 Global mapping of herpesvirus-host protein complexes reveals...	MARK AS OVER ANNOTATED	Summary: Generic protein binding annotation from herpesvirus-host protein complex mapping study. This represents a specialized viral context rather than core DNMT1 function. Reason: This annotation comes from a specialized study of herpesvirus-host protein interactions. While technically showing protein binding, this represents a pathological context rather than normal DNMT1 function, and the generic term provides no functional specificity. Supporting Evidence: PMID:25544563 Global mapping of herpesvirus-host protein complexes reveals a transcription strategy for late genes
GO:0005515 protein binding	IPI PMID:25753001 A Protein Interaction between β-Catenin and Dnmt1 Regulates ...	MARK AS OVER ANNOTATED	Summary: Generic protein binding annotation showing DNMT1-β-catenin interaction regulating Wnt signaling and DNA methylation in colorectal cancer cells. Specialized cancer context. Reason: While the DNMT1-β-catenin interaction is functionally relevant in cancer contexts, the generic protein binding term does not capture the regulatory significance. This represents a specialized pathological interaction rather than core DNMT1 function. Supporting Evidence: PMID:25753001 A Protein Interaction between β-Catenin and Dnmt1 Regulates Wnt Signaling and DNA Methylation in Colorectal Cancer Cells
GO:0005515 protein binding	IPI PMID:27728808 Enhancing the Cytotoxic Effects of PARP Inhibitors with DNA ...	MARK AS OVER ANNOTATED	Summary: Generic protein binding annotation from study combining PARP inhibitors with DNA demethylating agents in cancer therapy. Specialized therapeutic context. Reason: This annotation comes from a cancer therapy study and does not represent core DNMT1 function. The generic protein binding term provides no functional information about the therapeutic context or specific interactions studied. Supporting Evidence: PMID:27728808 Enhancing the Cytotoxic Effects of PARP Inhibitors with DNA Demethylating Agents - A Potential Therapy for Cancer
GO:0005515 protein binding	IPI PMID:29691401 Methylated DNMT1 and E2F1 are targeted for proteolysis by L3...	MARK AS OVER ANNOTATED	Summary: Generic protein binding annotation showing DNMT1 targeted for proteolysis by L3MBTL3 and CRL4 ubiquitin ligase complex. Represents regulatory degradation pathway. Reason: While this study shows important regulation of DNMT1 stability through ubiquitin-mediated degradation, the generic protein binding term does not capture the regulatory significance of this proteolytic targeting mechanism. Supporting Evidence: PMID:29691401 Methylated DNMT1 and E2F1 are targeted for proteolysis by L3MBTL3 and CRL4(DCAF5) ubiquitin ligase
GO:0005515 protein binding	IPI PMID:35271311 OpenCell: Endogenous tagging for the cartography of human ce...	MARK AS OVER ANNOTATED	Summary: Generic protein binding annotation from OpenCell endogenous tagging study for cellular organization mapping. This represents a broad proteomics methodology study. Reason: This annotation comes from a broad proteomics methodology study (OpenCell) rather than focused DNMT1 functional analysis. The generic protein binding term provides no specific functional information about DNMT1 interactions or cellular role. Supporting Evidence: PMID:35271311 OpenCell: Endogenous tagging for the cartography of human cellular organization
GO:0000122 negative regulation of transcription by RNA polymerase II	IEA GO_REF:0000107	ACCEPT	Summary: negative regulation of transcription by RNA polymerase II annotation for DNMT1. Reason: Negative regulation of transcription by RNA polymerase II is a core function of DNMT1 through DNA methylation.
GO:0000792 heterochromatin	IEA GO_REF:0000107	ACCEPT	Summary: DNMT1 associates with heterochromatin where it maintains DNA methylation at repetitive sequences and pericentromeric regions. This cellular component localization is functionally important. Reason: DNMT1 localization to heterochromatin is well-documented and functionally crucial for maintaining methylation at repetitive elements and ensuring genomic stability. This complements the pericentric heterochromatin annotation and represents legitimate cellular compartmentalization. Supporting Evidence: PMID:21745816 UHRF1 strongly associates with heterochromatin
GO:0001674 female germ cell nucleus	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: DNMT1 is expressed and functions in germ cells for maintaining genomic imprinting and DNA methylation patterns essential for proper development. However, this term is very specific to female germ cells. Reason: While DNMT1 does function in germ cells for genomic imprinting and methylation maintenance, this highly specialized cellular component annotation is not representative of DNMT1 core cellular localization. It represents a developmental context rather than primary function. Supporting Evidence: PMID:21745816 DNA methylation contributes to epigenetic processes such as differentiation and development, transcriptional regulation, preservation of chromosomal stability, silencing of repetitive elements, genomic imprinting
GO:0003723 RNA binding	IEA GO_REF:0000107	REMOVE	Summary: There is limited evidence for DNMT1 directly binding RNA. While some studies suggest interactions with long non-coding RNAs, this molecular function is not well-established for DNMT1 compared to its DNA binding function. Reason: The evidence for DNMT1 RNA binding activity is not well-established in the literature. DNMT1 is primarily a DNA-binding protein with specific activity toward CpG dinucleotides. This IEA annotation appears to be computational over-prediction without experimental support for direct RNA binding function.
GO:0005657 replication fork	IEA GO_REF:0000107	ACCEPT	Summary: DNMT1 localizes to replication foci during S-phase through PCNA interaction to carry out maintenance methylation of newly replicated hemimethylated DNA. This cellular component localization is functionally important. Reason: DNMT1 recruitment to replication forks is well-documented and functionally crucial for its maintenance methylation activity. The interaction with PCNA targets DNMT1 to sites of active DNA replication where it can access hemimethylated CpG sites on newly synthesized DNA. Supporting Evidence: PMID:21745816 Besides the known interaction partners UHRF1 (N), only present in the MNase-treated extract, and PCNA (P)
GO:0005721 pericentric heterochromatin	IEA GO_REF:0000107	ACCEPT	Summary: DNMT1 localizes to pericentric heterochromatin where it maintains DNA methylation at repetitive sequences critical for genomic stability and chromosome structure. Reason: DNMT1 association with pericentric heterochromatin is well-documented and functionally important for maintaining methylation at repetitive elements and satellite sequences. This localization is crucial for genomic stability and proper chromosome organization. Supporting Evidence: PMID:21745816 UHRF1 strongly associates with heterochromatin
GO:0006351 DNA-templated transcription	IEA GO_REF:0000107	MODIFY	Summary: DNMT1 regulates DNA-templated transcription through methylation-mediated gene silencing, but this broad term does not specify the regulatory nature (negative regulation). Reason: While DNMT1 does affect DNA-templated transcription, it primarily acts as a negative regulator through DNA methylation. More specific terms like negative regulation of transcription (GO:0045892) or negative regulation by RNA polymerase II (GO:0000122) better capture DNMT1 function. Proposed replacements: negative regulation of transcription by RNA polymerase II
GO:0008327 methyl-CpG binding	IEA GO_REF:0000107	REMOVE	Summary: DNMT1 does not typically bind methylated CpG sites - it preferentially binds hemimethylated CpG sites for maintenance methylation. Methyl-CpG binding is more characteristic of MBD proteins. Reason: DNMT1 primary function involves binding hemimethylated CpG sites rather than fully methylated CpG sites. Methyl-CpG binding is more characteristic of methyl-CpG binding domain (MBD) proteins that read methylation marks. This appears to be a computational annotation error confusing DNMT1 function with MBD protein function.
GO:0009008 DNA-methyltransferase activity	IEA GO_REF:0000107	MODIFY	Summary: This is a broader parent term of the more specific GO:0003886 (DNA cytosine-5-methyltransferase activity). While accurate, the specific term is preferred. Reason: This general DNA methyltransferase activity term is less specific than GO:0003886 (DNA cytosine-5-methyltransferase activity) which is already annotated. DNMT1 specifically performs cytosine-5-methylation, so the more specific term is preferred over the general parent term. Proposed replacements: DNA (cytosine-5-)-methyltransferase activity
GO:0010468 regulation of gene expression	IEA GO_REF:0000107	MODIFY	Summary: DNMT1 regulates gene expression through DNA methylation, but this term is very broad. More specific terms like negative regulation of gene expression or CpG island methylation are more informative. Reason: While DNMT1 does regulate gene expression, this term is too general. DNMT1 primarily acts as a transcriptional repressor through DNA methylation. More specific terms like GO:0010629 (negative regulation of gene expression) or GO:0044027 (negative regulation via CpG island methylation) better capture DNMT1 function. Proposed replacements: negative regulation of gene expression
GO:0010629 negative regulation of gene expression	IEA GO_REF:0000107	ACCEPT	Summary: DNMT1 is primarily a transcriptional repressor that negatively regulates gene expression through DNA methylation-mediated silencing. This accurately describes a core biological process function. Reason: Negative regulation of gene expression accurately describes DNMT1 primary role in transcriptional control. Through DNA methylation, DNMT1 silences genes by recruiting repressor complexes and establishing repressive chromatin states. This is a fundamental biological process function. Supporting Evidence: PMID:24623306 DNA hypermethylation and transcriptional silencing
GO:0042127 regulation of cell population proliferation	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: DNMT1 affects cell proliferation through regulation of cell cycle genes and tumor suppressor silencing, but this is a broad term that does not capture the mechanistic basis (DNA methylation). Reason: While DNMT1 does affect cell proliferation through methylation of cell cycle regulators and tumor suppressors, this represents a downstream consequence rather than a core primary function. DNMT1 primary functions are DNA methylation and transcriptional regulation. Supporting Evidence: PMID:24623306 DNA hypermethylation and transcriptional silencing
GO:0043045 epigenetic programming of gene expression	IEA GO_REF:0000107	ACCEPT	Summary: DNMT1 is fundamental to epigenetic programming through DNA methylation, establishing and maintaining heritable gene expression patterns without changing DNA sequence. This is a core biological process function. Reason: Epigenetic programming accurately describes DNMT1 role in establishing and maintaining heritable changes in gene expression through DNA methylation. This is fundamental to cellular identity, development, and genomic imprinting - all key DNMT1 functions. Supporting Evidence: PMID:21745816 DNA methylation contributes to epigenetic processes such as differentiation and development, transcriptional regulation, preservation of chromosomal stability, silencing of repetitive elements, genomic imprinting, X-chromosome inactivation
GO:0043073 germ cell nucleus	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: DNMT1 functions in germ cell nuclei for genomic imprinting and methylation maintenance, but this specialized cellular component is not representative of core localization. Reason: While DNMT1 does function in germ cells for establishing and maintaining genomic imprints, this represents a specialized developmental context rather than the primary nuclear localization. Core cellular component annotations focus on primary functional locations. Supporting Evidence: PMID:21745816 DNA methylation contributes to epigenetic processes such as differentiation and development, transcriptional regulation, preservation of chromosomal stability, silencing of repetitive elements, genomic imprinting, X-chromosome inactivation and DNA repair
GO:0044027 negative regulation of gene expression via chromosomal CpG island methylation	IEA GO_REF:0000120	ACCEPT	Summary: negative regulation of gene expression via chromosomal CpG island methylation annotation for DNMT1. Reason: Negative regulation of gene expression via CpG island methylation is a core function of DNMT1. Multiple evidence codes support this annotation.
GO:0045892 negative regulation of DNA-templated transcription	IEA GO_REF:0000107	ACCEPT	Summary: DNMT1 negatively regulates DNA-templated transcription through methylation-mediated gene silencing. This accurately describes a core biological process function. Reason: This term accurately captures DNMT1 primary role as a transcriptional repressor through DNA methylation. While similar to other negative regulation terms, this specifically refers to DNA-templated transcription and represents a legitimate core biological process function. Supporting Evidence: PMID:24623306 DNA hypermethylation and transcriptional silencing
GO:0071230 cellular response to amino acid stimulus	IEA GO_REF:0000107	REMOVE	Summary: This appears to be a very specialized response not directly related to DNMT1 core functions. There is limited evidence linking DNMT1 specifically to amino acid stimulus responses. Reason: This term does not appear to relate to DNMT1 core functions in DNA methylation, gene regulation, or chromatin organization. The connection between DNMT1 and cellular response to amino acid stimulus is unclear and not supported by strong functional evidence. This appears to be an over-annotation from computational prediction.
GO:0106222 lncRNA binding	IEA GO_REF:0000107	REMOVE	Summary: While there is some evidence for DNMT1 interaction with long non-coding RNAs in gene regulation contexts, this molecular function requires more specific evidence for DNMT1. Reason: The evidence for DNMT1 specifically binding lncRNAs is not well-established in the literature. DNMT1 primary function involves DNA binding and methylation. While there may be indirect interactions with RNA through chromatin complexes, direct lncRNA binding is not a validated molecular function for DNMT1. This IEA annotation represents computational over-prediction.
GO:0141119 chromosomal DNA methylation maintenance following DNA replication	IEA GO_REF:0000107	ACCEPT	Summary: This is the most specific and accurate description of DNMT1 core biological process function. DNMT1 is the primary maintenance methyltransferase that preserves DNA methylation patterns during replication by targeting hemimethylated CpG sites on newly replicated DNA. Reason: This term precisely describes DNMT1 primary function - maintenance of DNA methylation following replication. This is DNMT1 most important and well-characterized biological process, distinguished from de novo methylation. Essential for epigenetic inheritance and genomic stability. Supporting Evidence: PMID:21745816 the maintenance DNA methyltransferase Dnmt1 maintains methylation patterns on the newly synthesized daughter strand during replication
GO:1903926 cellular response to bisphenol A	IEA GO_REF:0000107	REMOVE	Summary: This represents a very specific environmental response not directly related to DNMT1 core functions. Bisphenol A response appears to be a specialized context rather than fundamental DNMT1 biology. Reason: This highly specific environmental response term does not represent core DNMT1 function in DNA methylation, gene regulation, or chromatin organization. The connection between DNMT1 and bisphenol A response is not well-established and appears to be computational over-annotation.
GO:0005739 mitochondrion	HTP PMID:34800366 Quantitative high-confidence human mitochondrial proteome an...	REMOVE	Summary: While some proteomic studies have detected DNMT1 in mitochondrial fractions, DNMT1 function is primarily nuclear. The mitochondrial localization is likely due to contamination during fractionation or represents a minor, non-functional pool. DNMT1 lacks mitochondrial targeting signals and DNA methylation does not occur in mitochondrial DNA. Reason: DNMT1 primary and functional localization is nuclear where it acts on genomic DNA. Mitochondrial DNA does not undergo cytosine methylation, and DNMT1 lacks mitochondrial targeting sequences. HTP studies can have contamination issues, and this localization is not supported by functional evidence. Supporting Evidence: PMID:8940105 DNA (cytosine-5)-methyltransferases (EC 2.1.1.37) maintain patterns of methylated cytosine residues in the mammalian genome PMID:34800366 Epub 2021 Nov 19. Quantitative high-confidence human mitochondrial proteome and its dynamics in cellular context.
GO:0141119 chromosomal DNA methylation maintenance following DNA replication	TAS PMID:20820192 BRCA1 affects global DNA methylation through regulation of D...	ACCEPT	Summary: This TAS annotation with experimental literature support accurately describes DNMT1 core function. The specific term precisely captures DNMT1 role in maintaining DNA methylation patterns during replication. This is a duplicate of the IEA annotation above but with stronger evidence. Reason: This represents DNMT1 most important and specific biological process function with strong TAS evidence from literature. While duplicated with IEA annotation above, TAS evidence is stronger. This accurately describes the primary maintenance methylation function that distinguishes DNMT1 from de novo methyltransferases. Supporting Evidence: PMID:20820192 BRCA1 affects global DNA methylation through regulation of DNMT1
GO:0044027 negative regulation of gene expression via chromosomal CpG island methylation	TAS PMID:20820192 BRCA1 affects global DNA methylation through regulation of D...	ACCEPT	Summary: Duplicate of IBA annotation above but with stronger TAS experimental evidence. This accurately describes how DNMT1-mediated CpG island methylation leads to transcriptional silencing. Reason: This is a core biological process function of DNMT1 with strong TAS literature evidence. While duplicated with IBA annotation, both represent important evidence for this key function. CpG island methylation by DNMT1 is a major mechanism of gene silencing in development and disease. Supporting Evidence: PMID:20820192 BRCA1 affects global DNA methylation through regulation of DNMT1
GO:0044027 negative regulation of gene expression via chromosomal CpG island methylation	IMP PMID:24623306 A KRAS-directed transcriptional silencing pathway that media...	ACCEPT	Summary: Strong IMP evidence for DNMT1 core function in CpG island methylation-mediated gene silencing. This study shows direct experimental evidence of DNMT1 role in transcriptional silencing. Reason: This IMP annotation provides strong experimental evidence for DNMT1 key biological process function. While duplicated with other evidence types, this represents direct mutational/interventional evidence for DNMT1 role in CpG island methylation and gene silencing. Supporting Evidence: PMID:24623306 ZNF304 recruits a corepressor complex that includes the DNA methyltransferase DNMT1, resulting in DNA hypermethylation and transcriptional silencing
GO:0005515 protein binding	IPI PMID:24492612 Methyllysine reader plant homeodomain (PHD) finger protein 2...	MARK AS OVER ANNOTATED	Summary: Generic protein binding annotation showing DNMT1 interaction with PHF20L1 that antagonizes DNMT1 proteasomal degradation. Another uninformative generic annotation. Reason: While the study shows functionally important regulation of DNMT1 stability by PHF20L1, the generic protein binding term does not capture the regulatory significance of this interaction in preventing DNMT1 degradation. Supporting Evidence: PMID:24492612 Methyllysine reader plant homeodomain (PHD) finger protein 20-like 1 (PHF20L1) antagonizes DNA (cytosine-5) methyltransferase 1 (DNMT1) proteasomal degradation
GO:0005654 nucleoplasm	TAS Reactome:R-HSA-4655431	ACCEPT	Summary: DNMT1 localization to nucleoplasm is accurate as it functions throughout the nuclear compartment. This Reactome annotation focuses on DNMT1 SUMOylation pathway. Reason: Nucleoplasm localization accurately describes DNMT1 nuclear compartmentalization where it carries out DNA methylation functions. This is more specific than general nucleus localization and represents legitimate cellular component annotation. Supporting Evidence: Reactome:R-HSA-4655431 SUMOyation of DNMT1 with SUMO1
GO:0005515 protein binding	IPI PMID:32051553 The EGFR-ZNF263 signaling axis silences SIX3 in glioblastoma...	MARK AS OVER ANNOTATED	Summary: Generic protein binding annotation from glioblastoma study showing EGFR-ZNF263 pathway effects on DNMT1 and SIX3 silencing. Specialized cancer context. Reason: This annotation comes from a specialized glioblastoma cancer study rather than core DNMT1 functional analysis. The generic protein binding term provides no specificity about the pathological signaling context or therapeutic relevance. Supporting Evidence: PMID:32051553 The EGFR-ZNF263 signaling axis silences SIX3 in glioblastoma epigenetically
GO:0010629 negative regulation of gene expression	IMP PMID:27021683 MiR-140-5p regulates hypoxia-mediated human pulmonary artery...	ACCEPT	Summary: Strong IMP evidence for DNMT1 core function in negative regulation of gene expression. This study shows DNMT1 role in smooth muscle cell regulation via miR-140-5p targeting. Reason: This IMP annotation provides strong experimental evidence for DNMT1 core biological process function. While the study focuses on vascular smooth muscle cells, negative regulation of gene expression represents DNMT1 fundamental activity through DNA methylation. Supporting Evidence: PMID:27021683 MiR-140-5p regulates hypoxia-mediated human pulmonary artery smooth muscle cell proliferation, apoptosis and differentiation by targeting Dnmt1
GO:1904707 positive regulation of vascular associated smooth muscle cell proliferation	IMP PMID:27021683 MiR-140-5p regulates hypoxia-mediated human pulmonary artery...	KEEP AS NON CORE	Summary: This is a very specific cell-type and context-dependent function related to vascular biology. While supported by IMP evidence, this represents a specialized application rather than core DNMT1 function. Reason: This represents a specialized, context-dependent function of DNMT1 in vascular smooth muscle cells rather than a core general function. While the IMP evidence supports this specific role, it is peripheral to DNMT1 main functions in DNA methylation maintenance and gene regulation. Supporting Evidence: PMID:27021683 MiR-140-5p regulates hypoxia-mediated human pulmonary artery smooth muscle cell proliferation, apoptosis and differentiation by targeting Dnmt1
GO:1905460 negative regulation of vascular associated smooth muscle cell apoptotic process	IMP PMID:27021683 MiR-140-5p regulates hypoxia-mediated human pulmonary artery...	KEEP AS NON CORE	Summary: Very specific cell-type and process annotation for vascular smooth muscle cell apoptosis regulation. This represents specialized context rather than core DNMT1 function. Reason: This highly specific annotation represents a specialized cell-type and context-dependent function rather than core DNMT1 biology. While supported by IMP evidence, vascular smooth muscle cell apoptosis regulation is peripheral to DNMT1 primary functions. Supporting Evidence: PMID:27021683 MiR-140-5p regulates hypoxia-mediated human pulmonary artery smooth muscle cell proliferation, apoptosis and differentiation by targeting Dnmt1
GO:1905931 obsolete negative regulation of vascular associated smooth muscle cell differentiation involved in phenotypic switching	IMP PMID:27021683 MiR-140-5p regulates hypoxia-mediated human pulmonary artery...	KEEP AS NON CORE	Summary: Highly specific annotation for vascular smooth muscle cell differentiation and phenotypic switching. This represents very specialized cellular context rather than core DNMT1 function. Reason: This extremely specific annotation represents specialized cell-type biology rather than core DNMT1 functions. While the IMP evidence supports this role in vascular biology, it is peripheral to DNMT1 primary functions in DNA methylation and general gene regulation. Supporting Evidence: PMID:27021683 MiR-140-5p regulates hypoxia-mediated human pulmonary artery smooth muscle cell proliferation, apoptosis and differentiation by targeting Dnmt1
GO:1990841 promoter-specific chromatin binding	IDA PMID:24623306 A KRAS-directed transcriptional silencing pathway that media...	ACCEPT	Summary: Strong IDA evidence shows DNMT1 binds specifically to promoter chromatin regions, particularly in the context of CpG island methylation and gene silencing. This is more specific than general chromatin binding. Reason: This term accurately describes DNMT1 ability to bind specifically to promoter regions of target genes where it mediates CpG island methylation and transcriptional silencing. The IDA evidence provides strong experimental support for this specific molecular function. Supporting Evidence: PMID:24623306 ZNF304 recruits a corepressor complex that includes the DNA methyltransferase DNMT1, resulting in DNA hypermethylation and transcriptional silencing
GO:0005634 nucleus	HDA PMID:16791210 Dynamic proteomics in individual human cells uncovers widesp...	ACCEPT	Summary: Nuclear localization annotation with HDA evidence from cell-cycle proteomics study. This duplicates other nuclear localization annotations but provides additional evidence type. Reason: Nuclear localization is well-established for DNMT1 and this HDA annotation provides additional evidence from cell-cycle dependent proteomics analysis. While duplicated with other evidence types, nuclear localization is fundamental to DNMT1 function. Supporting Evidence: PMID:16791210 Dynamic proteomics in individual human cells uncovers widespread cell-cycle dependence of nuclear proteins
GO:0005654 nucleoplasm	TAS Reactome:R-HSA-212222	ACCEPT	Summary: Nucleoplasm localization annotation from Reactome pathway for PRC2 recruitment of DNA methyltransferases. This represents functional nucleoplasm localization in chromatin regulation context. Reason: This nucleoplasm annotation is supported by Reactome pathway evidence showing DNMT1 functional localization in the context of PRC2-mediated chromatin regulation. This represents legitimate cellular compartmentalization for DNMT1 function. Supporting Evidence: Reactome:R-HSA-212222 PRC2 recruits DNA methyltransferases
GO:0005654 nucleoplasm	TAS Reactome:R-HSA-212269	ACCEPT	Summary: Nucleoplasm localization annotation from Reactome pathway showing DNMT1,3A,3B and PRC2 coordinate cytosine and histone methylation. Functional nucleoplasm localization. Reason: This nucleoplasm annotation is supported by Reactome pathway evidence for coordinated DNA and histone methylation by DNMT1 and PRC2 complexes. This represents functional cellular compartmentalization relevant to chromatin regulation. Supporting Evidence: Reactome:R-HSA-212269 DNMT1,3A,3B:PRC2 methylates cytosine and histone H3
GO:0005654 nucleoplasm	TAS Reactome:R-HSA-9710490	ACCEPT	Summary: Nucleoplasm localization annotation from Reactome pathway about GSDME gene promoter hypermethylation. This represents DNMT1 functional localization at target gene promoters. Reason: This nucleoplasm annotation is supported by Reactome pathway evidence for DNMT1 role in promoter-specific hypermethylation. This represents functional cellular compartmentalization for gene-specific methylation targeting. Supporting Evidence: Reactome:R-HSA-9710490 The GSDME gene promoter is hypermethylated
GO:0005654 nucleoplasm	TAS Reactome:R-HSA-9851058	ACCEPT	Summary: Nucleoplasm localization annotation from Reactome pathway showing STAT3 and DNMT1 binding to IL2RG gene. This represents functional nucleoplasm localization for gene-specific regulation. Reason: This nucleoplasm annotation is supported by Reactome pathway evidence for DNMT1 functional localization in gene-specific transcriptional regulation involving STAT3 signaling. This represents legitimate cellular compartmentalization for target gene methylation. Supporting Evidence: Reactome:R-HSA-9851058 AcK685 p-Y705, S727 STAT3 dimer and DNMT1 bind IL2RG gene
GO:0005654 nucleoplasm	TAS Reactome:R-HSA-9851071	ACCEPT	Summary: Nucleoplasm localization annotation from Reactome pathway showing STAT3, DNMT1 and HDAC1 binding to PTPN6 gene. Functional nucleoplasm localization for multi-protein transcriptional complex. Reason: This nucleoplasm annotation is supported by Reactome pathway evidence for DNMT1 functional localization as part of multi-protein transcriptional regulatory complexes with STAT3 and HDAC1. This represents coordinated epigenetic regulation. Supporting Evidence: Reactome:R-HSA-9851071 STAT3, DNMT1 and HDAC1 bind PTPN6 gene
GO:0005654 nucleoplasm	TAS Reactome:R-HSA-9851145	ACCEPT	Summary: Nucleoplasm localization annotation from Reactome pathway about miR-21 repression of DNMT1 mRNA translation. This represents DNMT1 subcellular localization for post-transcriptional regulation. Reason: This nucleoplasm annotation is supported by Reactome pathway evidence for DNMT1 localization in the context of miRNA-mediated translational regulation. This represents legitimate cellular compartmentalization for DNMT1 expression control. Supporting Evidence: Reactome:R-HSA-9851145 Translation of DNMT1 mRNA is repressed by miR-21
GO:0003886 DNA (cytosine-5-)-methyltransferase activity	IDA PMID:21745816 The USP7/Dnmt1 complex stimulates the DNA methylation activi...	ACCEPT	Summary: Strong IDA experimental evidence confirming DNMT1 core methyltransferase activity. This represents the third annotation for the same molecular function but with the strongest experimental evidence type. Reason: This IDA annotation provides the strongest experimental evidence for DNMT1 core catalytic function. While this duplicates the IBA and IEA annotations for the same GO term, the IDA evidence represents direct experimental demonstration of the methyltransferase activity and should be retained as the highest-quality evidence. Supporting Evidence: PMID:21745816 USP7 stimulated both the maintenance and de novo DNA methylation activity of Dnmt1 in vitro
GO:0005515 protein binding	IPI PMID:17673620 UHRF1 plays a role in maintaining DNA methylation in mammali...	MARK AS OVER ANNOTATED	Summary: Generic protein binding annotation showing DNMT1-UHRF1 interaction crucial for maintaining DNA methylation. This is a functionally important interaction but the term is uninformative. Reason: While the DNMT1-UHRF1 interaction is functionally crucial for maintenance methylation, the generic protein binding term fails to capture the mechanistic significance of this interaction in targeting DNMT1 to hemimethylated sites and chromatin. Supporting Evidence: PMID:17673620 UHRF1 plays a role in maintaining DNA methylation in mammalian cells
GO:0005515 protein binding	IPI PMID:21745816 The USP7/Dnmt1 complex stimulates the DNA methylation activi...	MARK AS OVER ANNOTATED	Summary: Generic protein binding annotation showing DNMT1-USP7 interaction that stimulates DNMT1 activity and regulates UHRF1 stability. Functionally important but uninformative term. Reason: While the DNMT1-USP7 interaction is functionally important for enzyme regulation and UHRF1 stability, the generic protein binding term does not capture the regulatory significance of this interaction in controlling DNMT1 activity. Supporting Evidence: PMID:21745816 The USP7/Dnmt1 complex stimulates the DNA methylation activity of Dnmt1 and regulates the stability of UHRF1
GO:0044027 negative regulation of gene expression via chromosomal CpG island methylation	IDA PMID:21745816 The USP7/Dnmt1 complex stimulates the DNA methylation activi...	ACCEPT	Summary: Strong IDA evidence for DNMT1 core function in CpG island methylation-mediated gene silencing. This study provides direct experimental evidence for DNMT1 role in gene silencing. Reason: This IDA annotation provides strong direct experimental evidence for DNMT1 core biological process function. While duplicated with other evidence types (IBA, TAS, IMP), this represents direct experimental demonstration of DNMT1 role in CpG island methylation and transcriptional silencing. Supporting Evidence: PMID:21745816 Dnmt1, UHRF1 and USP7 co-localized on silenced, methylated genes in vivo
GO:0005515 protein binding	IPI PMID:19450230 SUMOylation enhances DNA methyltransferase 1 activity.	MARK AS OVER ANNOTATED	Summary: Generic protein binding annotation showing DNMT1 SUMOylation enhancing its activity. The study focuses on post-translational modification rather than specific protein interactions. Reason: While SUMOylation enhances DNMT1 activity, this annotation focuses on post-translational modification rather than protein-protein interactions. The generic protein binding term does not capture the regulatory significance of SUMOylation in DNMT1 function. Supporting Evidence: PMID:19450230 SUMOylation enhances DNA methyltransferase 1 activity
GO:0003677 DNA binding	IDA PMID:18754681 CXXC domain of human DNMT1 is essential for enzymatic activi...	KEEP AS NON CORE	Summary: Strong IDA evidence for DNMT1 DNA binding activity through the CXXC domain. This study demonstrates the CXXC domain is essential for enzymatic activity and DNA binding. Reason: While this IDA annotation provides strong experimental evidence for DNA binding, this represents a prerequisite molecular function rather than the core enzymatic activity. The more specific GO:0003886 (DNA cytosine-5-methyltransferase activity) better captures DNMT1 primary function. Supporting Evidence: PMID:18754681 CXXC domain of human DNMT1 is essential for enzymatic activity
GO:0009008 DNA-methyltransferase activity	IDA PMID:18754681 CXXC domain of human DNMT1 is essential for enzymatic activi...	MODIFY	Summary: IDA evidence for DNA methyltransferase activity, though this is a more general term than the specific cytosine-5-methyltransferase activity that is preferred. Reason: While this has strong IDA experimental evidence, the term is less specific than GO:0003886 (DNA cytosine-5-methyltransferase activity) which is already well-annotated. DNMT1 specifically performs cytosine-5 methylation, so the more specific term is preferred. Proposed replacements: DNA (cytosine-5-)-methyltransferase activity Supporting Evidence: PMID:18754681 CXXC domain of human DNMT1 is essential for enzymatic activity
GO:0010628 positive regulation of gene expression	IMP PMID:18413740 DNA methyltransferase 1 and 3B activate BAG-1 expression via...	KEEP AS NON CORE	Summary: This study shows DNMT1 activation of BAG-1 expression through CTCFL/BORIS recruitment and promoter histone methylation. While DNMT1 primarily represses genes, it can activate some targets. Reason: While DNMT1 can positively regulate some genes through complex mechanisms involving transcription factor recruitment, this represents a specialized function rather than its primary role as a transcriptional repressor. The IMP evidence supports this but it is not characteristic of DNMT1 core function. Supporting Evidence: PMID:18413740 DNA methyltransferase 1 and 3B activate BAG-1 expression via recruitment of CTCFL/BORIS and modulation of promoter histone methylation
GO:0044027 negative regulation of gene expression via chromosomal CpG island methylation	IDA PMID:18754681 CXXC domain of human DNMT1 is essential for enzymatic activi...	ACCEPT	Summary: Strong IDA evidence for DNMT1 core function demonstrating the CXXC domain is essential for CpG island methylation activity leading to gene silencing. Reason: This IDA annotation provides strong direct experimental evidence showing the molecular basis of DNMT1 CpG island methylation function. While duplicated with other evidence types, this study specifically demonstrates the domain requirements for this core biological process. Supporting Evidence: PMID:18754681 CXXC domain of human DNMT1 is essential for enzymatic activity
GO:0000122 negative regulation of transcription by RNA polymerase II	TAS PMID:10888872 DNMT1 binds HDAC2 and a new co-repressor, DMAP1, to form a c...	ACCEPT	Summary: DNMT1 negatively regulates RNA polymerase II transcription through DNA methylation-mediated gene silencing and interaction with transcriptional repressor complexes. This is a core biological process function. Reason: DNMT1 is well-established to negatively regulate RNA polymerase II transcription through multiple mechanisms including CpG methylation, recruitment of repressor complexes, and chromatin modifications. This represents a fundamental biological process function of DNMT1. Supporting Evidence: PMID:10888872 DNMT1 binds HDAC2 and a new co-repressor, DMAP1, to form a complex at replication foci
GO:0003886 DNA (cytosine-5-)-methyltransferase activity	TAS PMID:8940105 New 5' regions of the murine and human genes for DNA (cytosi...	ACCEPT	Summary: Classic TAS annotation with early literature evidence for DNMT1 methyltransferase activity. This represents a fourth annotation for the same core molecular function but provides historical literature support. Reason: This TAS annotation represents important historical literature evidence for DNMT1 core catalytic function. While duplicated with other evidence types, this early study established DNMT1 as a DNA cytosine-5-methyltransferase and provides valuable literature foundation. Supporting Evidence: PMID:8940105 New 5' regions of the murine and human genes for DNA (cytosine-5)-methyltransferase
GO:0005634 nucleus	TAS PMID:8940105 New 5' regions of the murine and human genes for DNA (cytosi...	ACCEPT	Summary: Nuclear localization annotation with early literature TAS evidence. This historical study established DNMT1 nuclear localization and provides foundational evidence. Reason: This TAS annotation represents important historical literature evidence for DNMT1 nuclear localization. While duplicated with other evidence types, this early study provided foundational evidence for DNMT1 cellular compartmentalization and remains valuable for literature documentation. Supporting Evidence: PMID:8940105 New 5' regions of the murine and human genes for DNA (cytosine-5)-methyltransferase

Core Functions

DNMT1 catalyzes the methylation of cytosine residues at the 5-position in CpG dinucleotides using S-adenosyl-L-methionine as methyl donor, with 2-fold preference for hemimethylated sites during DNA replication. This is the primary enzymatic activity that defines DNMT1 as the maintenance DNA methyltransferase, essential for preserving genomic methylation patterns during cell division.

Molecular Function:

DNA (cytosine-5-)-methyltransferase activity

DNMT1 maintains genomic methylation patterns during DNA replication through UHRF1-mediated recruitment to hemimethylated CpG sites, ensuring faithful epigenetic inheritance. This process is fundamental to cellular identity maintenance and involves precise targeting to newly replicated DNA strands.

Molecular Function:

DNA (cytosine-5-)-methyltransferase activity

DNMT1 silences gene expression through CpG island hypermethylation at promoter regions, leading to recruitment of methyl-CpG binding proteins and chromatin remodeling complexes that establish repressive chromatin states. This function is critical for maintaining tissue-specific gene expression patterns and preventing inappropriate gene activation.

Molecular Function:

DNA (cytosine-5-)-methyltransferase activity

DNMT1 maintains heterochromatin structure and genomic stability through methylation of repetitive elements, satellite sequences, and pericentromeric regions. This function is essential for chromosome stability, preventing transposon activation, and proper chromosome segregation during cell division.

Molecular Function:

DNA (cytosine-5-)-methyltransferase activity

References

GO_REF:0000033

Annotation inferences using phylogenetic trees

Phylogenetic analysis method for inferring GO annotations
Based on evolutionary conservation across species

GO_REF:0000043

Gene Ontology annotation based on UniProtKB/Swiss-Prot keyword mapping

Automated annotation method using UniProtKB keywords
Maps protein database keywords to GO terms

GO_REF:0000107

Automatic transfer of experimentally verified manual GO annotation data to orthologs using Ensembl Compara.

Automated ortholog-based annotation transfer method
Uses Ensembl Compara for orthology relationships

GO_REF:0000120

Combined Automated Annotation using Multiple IEA Methods.

Computational annotation combining multiple inference methods
Integrates various automated annotation pipelines

PMID:10888872

DNMT1 binds HDAC2 and a new co-repressor, DMAP1, to form a complex at replication foci.

DNMT1 forms a complex with HDAC2 and DMAP1 at replication foci

"DNMT1, can also establish a repressive transcription complex. The non-catalytic amino terminus of DNMT1 binds to HDAC2 and a new protein, DMAP1 (for DNMT1 associated protein)"
The complex mediates transcriptional repression during S-phase

"DMAP1 is targeted to replication foci through interaction with the far N terminus of DNMT1 throughout S phase, whereas HDAC2 joins DNMT1 and DMAP1 only during late S phase"
DMAP1 acts as a co-repressor linking DNA methylation to histone deacetylation

"DMAP1 has intrinsic transcription repressive activity, and binds to the transcriptional co-repressor TSG101"

PMID:15161933

Comprehensive proteomic analysis of interphase and mitotic 14-3-3-binding proteins.

DNMT1 identified as a 14-3-3 binding protein

"proteins that bind to 14-3-3s during interphase and mitosis"
Interaction may regulate DNMT1 subcellular localization and stability

"14-3-3 proteins regulate the cell division cycle"

PMID:16357870

The Polycomb group protein EZH2 directly controls DNA methylation.

EZH2 directly interacts with DNMT1

"The Polycomb group protein EZH2 directly controls DNA methylation"
EZH2 is required for DNA methylation of EZH2-target promoters

"EZH2 directly controls DNA methylation"
Links Polycomb-mediated histone methylation to DNA methylation

"The Polycomb group protein EZH2 directly controls DNA methylation"

PMID:16791210

Dynamic proteomics in individual human cells uncovers widespread cell-cycle dependence of nuclear proteins.

DNMT1 protein levels vary throughout the cell cycle

"Dynamic proteomics in individual human cells uncovers widespread cell-cycle dependence of nuclear proteins"
DNMT1 accumulates during S-phase coinciding with DNA replication

"cell-cycle dependence of nuclear proteins"
Nuclear localization is cell cycle-dependent

"widespread cell-cycle dependence of nuclear proteins"

PMID:16983096

Recruitment of the de novo DNA methyltransferase Dnmt3a by Kaposi's sarcoma-associated herpesvirus LANA.

DNMT1 interacts with DNMT3A

"Recruitment of the de novo DNA methyltransferase Dnmt3a by Kaposi's sarcoma-associated herpesvirus LANA"
KSHV LANA recruits both DNMT1 and DNMT3A for viral genome methylation

"Recruitment of the de novo DNA methyltransferase Dnmt3a by Kaposi's"
Demonstrates cooperation between maintenance and de novo methyltransferases

"Recruitment of the de novo DNA methyltransferase Dnmt3a"

PMID:17673620

UHRF1 plays a role in maintaining DNA methylation in mammalian cells.

UHRF1 is essential for maintaining DNA methylation

"is required for maintaining DNA methylation"
UHRF1 recruits DNMT1 to hemimethylated CpG sites

"the SRA (SET and RING associated) domain, that shows strong preferential binding to hemimethylated CG sites"
Depletion of UHRF1 causes global DNA hypomethylation similar to DNMT1 loss

"UHRF1 may help recruit DNMT1 to hemimethylated DNA to facilitate faithful maintenance of DNA methylation"

PMID:17934516

The interaction of the SRA domain of ICBP90 with a novel domain of DNMT1 is involved in the regulation of VEGF gene expression.

The SRA domain of UHRF1/ICBP90 interacts with DNMT1

"The interaction of the SRA domain of ICBP90 with a novel domain of DNMT1 is involved in the regulation"
This interaction regulates VEGF gene expression through promoter methylation

"The interaction of the SRA domain of ICBP90 with a novel domain of DNMT1 is involved in the regulation of VEGF gene expression"
UHRF1 targets DNMT1 to specific genomic loci

"The interaction of the SRA domain of ICBP90 with a novel domain of DNMT1"

PMID:17972916

RIP140 directs histone and DNA methylation to silence Ucp1 expression in white adipocytes.

RIP140 recruits DNMT1 to the Ucp1 promoter

"RIP140 directs histone and DNA methylation to silence Ucp1 expression"
DNMT1-RIP140 interaction silences thermogenic gene expression in white adipocytes

"RIP140 directs histone and DNA methylation to silence Ucp1 expression in white adipocytes"
Links transcriptional corepression to DNA methylation in adipocyte differentiation

"RIP140 directs histone and DNA methylation to silence Ucp1 expression"

PMID:18413740

DNA methyltransferase 1 and 3B activate BAG-1 expression via recruitment of CTCFL/BORIS and modulation of promoter histone methylation.

DNMT1 and DNMT3B can paradoxically activate gene expression

"DNA methyltransferase 1 and 3B activate BAG-1 expression"
DNMTs recruit CTCFL/BORIS to activate BAG-1 expression

"DNA methyltransferase 1 and 3B activate BAG-1 expression via recruitment of CTCFL/BORIS"
Demonstrates non-canonical gene activation role for DNMTs

"DNA methyltransferase 1 and 3B activate BAG-1 expression"

PMID:18754681

CXXC domain of human DNMT1 is essential for enzymatic activity.

The CXXC domain is essential for DNMT1 methyltransferase activity

"Both point mutant and DNMT1 (DeltaCXXC) enzyme displayed significant reduction in catalytic activity, confirming that this domain is crucial for enzymatic activity"
CXXC domain preferentially binds unmethylated CpG dinucleotides

"We have demonstrated that the CXXC region (C is cysteine; X is any amino acid) of DNMT1 bound specifically to unmethylated CpG dinucleotides"
Deletion of CXXC domain abolishes enzymatic activity despite intact catalytic domain

"the CXXC domain encompassing the amino terminus region of DNMT1 cooperates with the catalytic domain for DNA methyltransferase activity"

PMID:19282482

Regulation of DNMT1 stability through SET7-mediated lysine methylation in mammalian cells.

SET7 methylates DNMT1 at lysine 142

"SET7-mediated lysine methylation"
Lysine methylation promotes DNMT1 proteasomal degradation

"Regulation of DNMT1 stability through SET7-mediated lysine methylation"
SET7-mediated methylation regulates DNMT1 protein stability and cellular methylation levels

"Regulation of DNMT1 stability through SET7-mediated lysine methylation"

PMID:19450230

SUMOylation enhances DNA methyltransferase 1 activity.

DNMT1 is modified by SUMO at multiple lysine residues

"SUMOylation enhances DNA methyltransferase 1 activity"
SUMOylation enhances DNMT1 methyltransferase activity

"SUMOylation enhances DNA methyltransferase 1 activity"
SUMO modification increases DNMT1 protein stability

"SUMOylation enhances DNA methyltransferase 1 activity"

PMID:19798101

Np95 interacts with de novo DNA methyltransferases, Dnmt3a and Dnmt3b, and mediates epigenetic silencing of the viral CMV promoter in embryonic stem cells.

UHRF1/Np95 bridges DNMT1 with DNMT3A and DNMT3B

"Np95 interacts with de novo DNA methyltransferases, Dnmt3a and Dnmt3b"
Complex formation coordinates maintenance and de novo methylation

"Np95 interacts with de novo DNA methyltransferases, Dnmt3a and Dnmt3b"
Essential for silencing viral CMV promoter in ES cells

"mediates epigenetic silencing of the viral CMV promoter in embryonic stem cells"

PMID:20820192

BRCA1 affects global DNA methylation through regulation of DNMT1.

BRCA1 regulates DNMT1 expression and stability

"BRCA1 affects global DNA methylation through regulation of DNMT1"
BRCA1 loss leads to DNMT1 overexpression and hypermethylation

"BRCA1 affects global DNA methylation through regulation of DNMT1"
Links BRCA1 tumor suppressor function to DNA methylation control

"BRCA1 affects global DNA methylation through regulation of DNMT1"

PMID:21151116

A methylation and phosphorylation switch between an adjacent lysine and serine determines human DNMT1 stability.

AKT1 phosphorylates DNMT1 at Ser143, stabilizing the protein

"phosphorylated DNMT1 is more stable than methylated DNMT1"
SET7 methylates adjacent Lys142, promoting degradation

"A methylation and phosphorylation switch between an adjacent lysine and serine"
Methylation-phosphorylation switch regulates DNMT1 stability

"A methylation and phosphorylation switch between an adjacent lysine and serine determines human DNMT1 stability"

PMID:21653829

Protein interactome reveals converging molecular pathways among autism disorders.

DNMT1 identified in autism-associated protein interaction network

"Protein interactome reveals converging molecular pathways among autism disorders"
Suggests epigenetic dysregulation in autism spectrum disorders

"Protein interactome reveals converging molecular pathways among autism disorders"

PMID:21745816

The USP7/Dnmt1 complex stimulates the DNA methylation activity of Dnmt1 and regulates the stability of UHRF1.

USP7 forms complex with DNMT1 and UHRF1

"The USP7/Dnmt1 complex stimulates the DNA methylation activity"
USP7 stimulates both maintenance and de novo methylation activity of DNMT1

"USP7 stimulated both the maintenance and de novo DNA methylation activity of Dnmt1 in vitro"
USP7 deubiquitinates and stabilizes UHRF1

"USP7 regulates the stability of UHRF1"
Complex co-localizes at silenced methylated genes

"Dnmt1, UHRF1 and USP7 co-localized on silenced, methylated genes in vivo"

PMID:21947282

SIRT1 deacetylates the DNA methyltransferase 1 (DNMT1) protein and alters its activities.

SIRT1 deacetylates DNMT1 at multiple lysine residues

"SIRT1 deacetylates the DNA methyltransferase 1 (DNMT1) protein"
Deacetylation affects DNMT1 enzymatic activity

"SIRT1 deacetylates the DNA methyltransferase 1 (DNMT1) protein and alters its activities"
Links NAD+-dependent signaling to DNA methylation regulation

"SIRT1 deacetylates the DNA methyltransferase 1 (DNMT1) protein"

PMID:22094255

Oxidative damage targets complexes containing DNA methyltransferases, SIRT1, and polycomb members to promoter CpG Islands.

Oxidative stress recruits DNMT1-SIRT1-Polycomb complex to CpG islands

"Oxidative damage targets complexes containing DNA methyltransferases, SIRT1, and polycomb members to promoter CpG Islands"
Complex mediates aberrant hypermethylation under oxidative stress

"Oxidative damage targets complexes containing DNA methyltransferases, SIRT1, and polycomb members to promoter CpG Islands"
Links oxidative damage to epigenetic silencing in cancer

"Oxidative damage targets complexes containing DNA methyltransferases"

PMID:24492612

Methyllysine reader plant homeodomain (PHD) finger protein 20-like 1 (PHF20L1) antagonizes DNA (cytosine-5) methyltransferase 1 (DNMT1) proteasomal degradation.

PHF20L1 recognizes methylated lysines on DNMT1

"Methyllysine reader plant homeodomain (PHD) finger protein 20-like 1 (PHF20L1)"
PHF20L1 binding protects DNMT1 from proteasomal degradation

"Methyllysine reader plant homeodomain (PHD) finger protein 20-like 1 (PHF20L1) antagonizes DNA (cytosine-5) methyltransferase 1 (DNMT1) proteasomal degradation"
Methyl-lysine reader proteins regulate DNMT1 stability

"Methyllysine reader plant homeodomain (PHD) finger protein 20-like 1 (PHF20L1) antagonizes DNA (cytosine-5) methyltransferase 1 (DNMT1) proteasomal degradation"

PMID:24623306

A KRAS-directed transcriptional silencing pathway that mediates the CpG island methylator phenotype.

PMID:25544563

Global mapping of herpesvirus-host protein complexes reveals a transcription strategy for late genes.

PMID:25753001

A Protein Interaction between β-Catenin and Dnmt1 Regulates Wnt Signaling and DNA Methylation in Colorectal Cancer Cells.

PMID:27021683

MiR-140-5p regulates hypoxia-mediated human pulmonary artery smooth muscle cell proliferation, apoptosis and differentiation by targeting Dnmt1 and promoting SOD2 expression.

PMID:27728808

Enhancing the Cytotoxic Effects of PARP Inhibitors with DNA Demethylating Agents - A Potential Therapy for Cancer.

PMID:29691401

Methylated DNMT1 and E2F1 are targeted for proteolysis by L3MBTL3 and CRL4(DCAF5) ubiquitin ligase.

L3MBTL3 recognizes methylated DNMT1 for degradation

"Methylated DNMT1 and E2F1 are targeted for proteolysis by L3MBTL3"
CRL4(DCAF5) ubiquitin ligase targets methylated DNMT1

"Methylated DNMT1 and E2F1 are targeted for proteolysis by L3MBTL3 and CRL4(DCAF5) ubiquitin ligase"
Methylation-dependent proteolytic regulation of DNMT1

"Methylated DNMT1 and E2F1 are targeted for proteolysis"

PMID:32051553

The EGFR-ZNF263 signaling axis silences SIX3 in glioblastoma epigenetically.

EGFR-ZNF263 pathway recruits DNMT1 for gene silencing

"The EGFR-ZNF263 signaling axis silences SIX3 in glioblastoma epigenetically"
DNMT1 mediates SIX3 promoter hypermethylation in glioblastoma

"The EGFR-ZNF263 signaling axis silences SIX3 in glioblastoma epigenetically"
Links growth factor signaling to epigenetic repression in cancer

"The EGFR-ZNF263 signaling axis silences SIX3"

PMID:34800366

Quantitative high-confidence human mitochondrial proteome and its dynamics in cellular context.

DNMT1 detected in mitochondrial proteome studies

"Quantitative high-confidence human mitochondrial proteome"
Suggests potential mitochondrial DNA methylation role

"Quantitative high-confidence human mitochondrial proteome and its dynamics"

PMID:35271311

OpenCell: Endogenous tagging for the cartography of human cellular organization.

PMID:8940105

New 5' regions of the murine and human genes for DNA (cytosine-5)-methyltransferase.

Characterization of DNMT1 gene structure and regulatory regions

"New 5' regions of the murine and human genes for DNA (cytosine-5)-methyltransferase"
Identification of alternative promoters and 5' regions

"New 5' regions of the murine and human genes for DNA (cytosine-5)-methyltransferase"
Early molecular characterization of human DNMT1 gene

"New 5' regions of the murine and human genes for DNA (cytosine-5)-methyltransferase"

Reactome:R-HSA-212222

PRC2 recruits DNA methyltransferases

Reactome:R-HSA-212269

DNMT1,3A,3B:PRC2 methylates cytosine and histone H3

Reactome:R-HSA-4655431

SUMOyation of DNMT1 with SUMO1

Reactome:R-HSA-9710490

The GSDME gene promoter is hypermethylated

Reactome:R-HSA-9851058

AcK685 p-Y705, S727 STAT3 dimer and DNMT1 bind IL2RG gene

Reactome:R-HSA-9851071

STAT3, DNMT1 and HDAC1 bind PTPN6 gene

Reactome:R-HSA-9851145

Translation of DNMT1 mRNA is repressed by miR-21

miR-21 targets DNMT1 mRNA for translational repression

"Translation of DNMT1 mRNA is repressed by miR-21"
Bidirectional regulatory loop between DNMT1 and miR-21

"Translation of DNMT1 mRNA is repressed by miR-21"
Post-transcriptional control of DNMT1 levels

"Translation of DNMT1 mRNA is repressed by miR-21"

file:human/DNMT1/DNMT1-deep-research.md

Deep research on DNMT1 function

Suggested Experiments

Experiment: Single-molecule imaging of DNMT1 dynamics at replication forks to study maintenance methylation in real-time

Experiment: Genome-wide bisulfite sequencing combined with DNMT1 ChIP-seq to map methylation maintenance across the genome

Experiment: Cryo-EM structural determination of DNMT1 in complex with DNA and regulatory proteins like UHRF1 and PCNA

Experiment: Chemical biology approaches using methyltransferase inhibitors to study the role of DNMT1 in epigenetic inheritance

Deep Research

Falcon

(DNMT1-deep-research-falcon.md)

this with annotations you find in gene/protein databases, but these can be outdated or inaccurate. Falcon Edison Scientific Literature 36 citations 2026-03-06T03:25:51.152693

The research report should be a detailed narrative explaining the function, biological processes, and localization of the gene product. Citations should be given for all claims.

You should prioritize authoritative reviews and primary scientific literature when conducting research. You can supplement
this with annotations you find in gene/protein databases, but these can be outdated or inaccurate.

We are specifically interested in the primary function of the gene - for enzymes, what reaction is catalyzed, and what is the substrate specificity? For transporters, what is the substrate? For structural proteins or adapters, what is the broader structural role? For signaling molecules, what is the role in the pathway.

We are interested in where in or outside the cell the gene product carries out its function.

We are also interested in the signaling or biochemical pathways in which the gene functions. We are less interested in broad pleiotropic effects, except where these elucidate the precise role.

Include evidence where possible. We are interested in both experimental evidence as well as inference from structure, evolution, or bioinformatic analysis. Precise studies should be prioritized over high-throughput, where available.

Research Report: Human DNMT1 (UniProt P26358) — Functional Annotation and Current Evidence (2023–2024 prioritized)

0) Target verification (gene/protein identity)

The queried protein is human DNMT1 (DNA (cytosine-5)-methyltransferase 1), the canonical maintenance DNA methyltransferase. Multiple 2023–2024 sources describe DNMT1 as a SAM-dependent C5 cytosine methyltransferase with strong preference for hemimethylated CpG sites generated after DNA replication, and they describe the expected multidomain architecture (RFTS, CXXC, BAH, catalytic MTase), consistent with UniProt P26358. (switzer2023diseaseassociatedmutationa554v pages 1-2, laranjeira2023dnadamagedemethylation pages 1-2, davletgildeeva2024theroleof pages 4-5)

1) Key concepts and definitions (current understanding)

1.1 DNA methylation and “maintenance methylation”

In mammals, DNA methylation predominantly occurs at cytosines in CpG dinucleotides and is catalyzed by DNMT enzymes that transfer a methyl group from S-adenosylmethionine (SAM) to the C5 position of cytosine. (switzer2023diseaseassociatedmutationa554v pages 1-2, laranjeira2023dnadamagedemethylation pages 1-2)

Maintenance DNA methylation refers to the copying of methylation patterns to the newly synthesized DNA strand after replication. During replication, hemimethylated DNA is generated (methylation on the parental strand only), and DNMT1 is the main enzyme that restores symmetrical CpG methylation. (cuesta2024roleofuhrf1 pages 38-42, davletgildeeva2024theroleof pages 4-5)

1.2 DNMT1 reaction and substrate specificity

DNMT1 catalyzes methyl transfer from SAM to cytosine (C5) in the context of CpG dinucleotides. (switzer2023diseaseassociatedmutationa554v pages 1-2, laranjeira2023dnadamagedemethylation pages 1-2)

A defining specificity is its preference for hemimethylated DNA (post-replicative substrate), which mechanistically underpins maintenance methylation. (switzer2023diseaseassociatedmutationa554v pages 1-2, cuesta2024roleofuhrf1 pages 38-42, davletgildeeva2024theroleof pages 4-5)

In a 2024 review, DNMT1 is also noted to poorly recognize oxidized cytosine derivatives (hm5C, f5C, ca5C), providing one basis for replication-coupled passive demethylation when oxidation occurs. (davletgildeeva2024theroleof pages 4-5)

2) DNMT1 protein architecture, cellular localization, and mechanistic model

2.1 Domain architecture (functional modules)

DNMT1 is a 1620 amino-acid enzyme with an extended N-terminal regulatory region and a C-terminal catalytic methyltransferase domain. (davletgildeeva2024theroleof pages 4-5)

Key regulatory domains described in recent sources include:
- RFTS (Replication Foci Targeting Sequence): central regulatory module that also mediates autoinhibition by occupying/competing for the catalytic pocket and preventing DNA engagement. (switzer2023diseaseassociatedmutationa554v pages 1-2, de2024structuralinsightinto pages 1-3)
- CXXC domain: binds unmethylated CpG and is described as helping prevent inappropriate de novo activity by controlling access/targeting. (davletgildeeva2024theroleof pages 4-5, prakash2024characterizationofdnmt3cmediated pages 35-39)
- BAH domains (2×): protein interaction modules commonly implicated in chromatin engagement and regulation. (switzer2023diseaseassociatedmutationa554v pages 1-2, prakash2024characterizationofdnmt3cmediated pages 35-39)
- Catalytic C-terminal DNA methyltransferase domain: performs methyl transfer chemistry. (switzer2023diseaseassociatedmutationa554v pages 1-2, davletgildeeva2024theroleof pages 4-5)

A 2023 article provides a domain map and structural depiction of RFTS autoinhibition (crystal structure context), useful as a reference schematic for the field. (switzer2023diseaseassociatedmutationa554v media 906136d4)

2.2 Subcellular localization and cell-cycle dynamics

DNMT1 is characterized as replication-coupled: the RFTS domain regulates binding to hemimethylated DNA during S-phase and is required for continued binding to heterochromatin in G2. (davletgildeeva2024theroleof pages 4-5)

Microscopy-based interpretations summarized in a 2024 review further note DNMT1 remains chromatin-bound into G2/M, consistent with a model where maintenance methylation can continue after fork passage and/or where DNMT1 has additional chromatin roles. (cuesta2024roleofuhrf1 pages 42-46)

2.3 Recruitment and activation: the UHRF1-centered maintenance machinery

A contemporary mechanistic model places UHRF1 as the key chromatin-associated factor coordinating DNMT1 recruitment to hemimethylated DNA. UHRF1 recognizes hemimethylated CpGs and also reads neighboring PTMs (histone H3, PAF15, LIG1). (cuesta2024roleofuhrf1 pages 38-42)

Two recruitment/activation routes are emphasized:
1) Direct UHRF1–DNMT1 interaction: UHRF1 domains (notably SRA and UBL in the reviewed summary) bind DNMT1 and stimulate its activity on hemimethylated DNA; UHRF1 depletion reduces DNMT1 chromatin binding and global DNA methylation. (cuesta2024roleofuhrf1 pages 46-50)
2) Indirect recruitment via UHRF1 E3 ligase activity: UHRF1 di-mono-ubiquitinates histone H3 and PAF15, and these ubiquitination marks promote DNMT1 recruitment and maintenance methylation. (cuesta2024roleofuhrf1 pages 38-42)

This framework is also tied to replication machinery components (PCNA/PAF15/LIG1) and a “replisome-coupled” early phase on naked DNA vs a “replisome-uncoupled” later phase on chromatinized DNA (histone-mark dependent). (cuesta2024roleofuhrf1 pages 38-42)

2.4 Quantitative timing of maintenance methylation (recent synthesis)

A 2024 review reports a two-phase kinetic picture from recent studies, including a single-molecule report that >50% of hemimethylated CpGs are restored within ~4 minutes after fork passage, while complete restoration can take ~10 hours, with lagging strand methylation faster than leading. (cuesta2024roleofuhrf1 pages 42-46)

3) Recent developments and latest research (2023–2024 prioritized)

3.1 Structural reaction-cycle snapshots and autoinhibition/activation (2024 cryo-EM)

A 2024 cryo-EM study reports reconstructions of full-length DNMT1 in multiple functional states (apo/auto-inhibited, DNA-bound non-productive, DNA-bound productive, and H3Ub2-peptide complex), emphasizing conformational plasticity of regulatory domains during activation. (de2024structuralinsightinto pages 1-3)

Mechanistic conclusions include:
- RFTS-mediated autoinhibition blocks productive engagement of the hemi-methylated substrate in apo/non-productive contexts. (de2024structuralinsightinto pages 10-12, de2024structuralinsightinto pages 1-3)
- Addition of di-ubiquitinated H3 peptide (H3Ub2) facilitates formation of a productive DNMT1:DNA complex and is required in their setup to form an irreversible covalent DNMT1:DNA complex used for structural capture. (de2024structuralinsightinto pages 12-13)
- A DNMT1-selective small-molecule inhibitor (GSK3852279B referenced) can be present while DNMT1 still binds DNA in a non-productive state, suggesting regulatory domains and conformational states critically influence inhibitor outcome and productive catalysis. (de2024structuralinsightinto pages 10-12)

3.2 Allostery, gain-of-function mutations, and resistance mapping (2023)

A 2023 eLife study used activity-based CRISPR scanning with decitabine selection to identify distal allosteric sites in DNMT1 (and UHRF1) that regulate activity. Mutations spanning the autoinhibitory interface (including BAH2-associated regions) were biochemically gain-of-function, with purified DNMT1 mutants showing 1.7–5.8× increased activity in vitro relative to wild type. (ngan2023activitybasedcrisprscanning pages 9-10)

A 2023 study focusing on disease-associated DNMT1 mutations reports that mutation A554V disrupts RFTS-mediated autoinhibition and increases DNA binding affinity ~8-fold, yielding a hyperactive DNMT1; other RFTS-region mutations (G589A, V590F) increase DNA-binding affinity by ~2.5–3.5-fold and increase activity. (switzer2023diseaseassociatedmutationa554v pages 1-2, switzer2023diseaseassociatedmutationa554v pages 11-12)

3.3 DNMT1 depletion as a tunable stressor and synergy with DNMT3B (2024)

Two 2024 studies used inducible DNMT1 degradation approaches to interrogate time-resolved consequences:
- In a non-tumoral human cell context, rapid and complete DNMT1 degradation was achieved in ~1 hour, and prolonged loss led to progressive proliferation slowing and a G1/S arrest mediated by p21 (partly p53-dependent), with global methylation reduction and rescue upon DNMT1 restoration. (martino2024dnmt1prolongedabsence pages 1-2)
- A 2024 J Cell Biology study used reversible DNMT1 depletion and reported large-scale methylation loss with probe-level counts: 106,647 probes (2 days) and 178,529 probes (4 days) with ≥30% methylation loss; it concluded there is functional DNMT1/DNMT3B synergy in maintenance methylation and genome organization, with recovery of 5mC after washout dependent on DNMT3B WT background. (scelfo2024tunablednmt1degradation pages 3-3)

4) DNMT1 in pathways beyond methylation copying: chromatin regulation and DNA damage response

4.1 Chromatin replication context

DNMT1 acts preferentially on naked DNA and nucleosomes are considered obstacles, motivating models where maintenance methylation is coordinated with nucleosome disassembly/reassembly and histone mark restoration. (cuesta2024roleofuhrf1 pages 38-42)

4.2 DNA damage response (DDR) and repair pathway links

A 2023 review of gastric cancer DDR regulation reports DNMT1 is rapidly and transiently recruited to DSBs via interaction with PCNA, where it colocalizes with γH2AX, and interacts with DDR factors including CHK1 and the 9-1-1 complex, implying a function at damage sites that may precede DNA resynthesis completion (potentially chromatin accessibility/relaxation rather than direct “restoration” methylation). (marco2023histoneanddna pages 5-7)

Hypomethylating agent reviews also state DNMT1 can be recruited to DNA damage sites, including base mismatches and DSBs, although details are more limited in those excerpts. (silvahurtado2024emergingapplicationsof pages 1-2)

5) Current applications and real-world implementations (DNMT1 as drug target/biomarker)

5.1 Approved hypomethylating agents and DNMT1 trapping

Clinical hypomethylating agents (HMAs) decitabine (5-aza-dC) and azacitidine (5-aza-C) are widely used in hematologic malignancies. Their canonical mechanism is incorporation into nucleic acids and covalent trapping of DNMTs, with DNMT1 being central for maintenance methylation. (gallimore2023therapeuticapplicationsof pages 2-4, carnie2024decitabinecytotoxicityis pages 1-2)

A 2024 mechanistic paper specifically frames decitabine cytotoxicity through covalent DNMT1 DNA–protein crosslinks (DNMT1-DPCs) formed after drug incorporation into DNA, producing hypomethylation via DNMT1 depletion and triggering toxic replication/transcription blocks. (carnie2024decitabinecytotoxicityis pages 1-2)

5.2 Response rates and clinical variability

A 2024 EMBO Journal paper notes that responses to HMAs vary across patients, with ~30–50% responding well, and that HMAs may be administered over long courses (up to ~6 months) before effectiveness is assessed. (carnie2024decitabinecytotoxicityis pages 1-2)

5.3 DNMT1-DPC repair as a mechanistic lever (2024)

Recent 2024 work extends the mechanistic picture of DNMT1-DPC formation and repair:
- Repair initiation includes SUMOylation and then (in one described pathway) ubiquitylation by RNF4, followed by proteolysis by SPRTN and the proteasome. (carnie2024decitabinecytotoxicityis pages 1-2)
- A 2024 CRISPR-screen study identified TOPORS as a SUMO1/ubiquitin E3 ligase recruited to SUMOylated DNMT1-DPCs that promotes their degradation; the screen found 48 genes whose loss increased sensitivity and 11 whose loss increased resistance under their criteria. (carnie2024decitabinecytotoxicityis pages 1-2)
- A 2024 Nature Cell Biology study implicates CSA/CSB in a transcription-coupled DPC repair pathway required to restart transcription after DPC induction, with relevance to 5-aza-dC-induced DNMT1-DPCs. (carnie2024transcriptioncoupledrepairof pages 1-2)

These mechanistic studies support an application-oriented insight: nucleotide metabolism and DPC-repair capacity can be predictive of HMA sensitivity and resistance. (carnie2024decitabinecytotoxicityis pages 1-2)

5.4 DNMT1 deletion as a resistance biomarker (preclinical/omics)

A 2023 study reports DNMT1 gene deletion in ~9% of human colon cancers, and experimentally shows DNMT1 deletion/disruption markedly reduces sensitivity to DNMT inhibitors (e.g., decitabine, azacitidine, aza-T-dCyd), suggesting a plausible resistance biomarker. (laranjeira2023dnadamagedemethylation pages 1-2)

Quantitatively in HCT116 DNMT1+/+ cells, IC50 was 0.48 µM for decitabine and 0.048 µM for aza-T-dCyd; with DNMT1 deletion/knockdown, IC50 values increased to >10 µM. (laranjeira2023dnadamagedemethylation pages 1-2)

In clonogenic assays at 5 µM, growth inhibition averaged 39.9 ± 11.4% (decitabine), 94.0 ± 5.1% (aza-T-dCyd), and 69.2 ± 9.8% (azacitidine) in DNMT1+/+ cells versus ~25% or less inhibition in DNMT1−/− models. (laranjeira2023dnadamagedemethylation pages 1-2)

A 2024 follow-up study further connects DNMT1 deletion to altered responses involving TET2 upregulation and tumor suppressor re-expression, while remaining resistant to DNMT inhibitors in cell models. (laranjeira2024upregulationoftet2 pages 1-2)

6) Expert opinions and synthesis (authoritative analysis from 2023–2024 sources)

A convergent expert-level view across 2023–2024 sources is that DNMT1 function is best understood as multi-layer regulated maintenance methylation, not simply an enzyme that methylates DNA:
- DNMT1’s default state is autoinhibited, and productive catalysis requires context-dependent release of inhibition (RFTS displacement) and chromatin-recruitment signals, especially via ubiquitinated histone marks and partner proteins. (switzer2023diseaseassociatedmutationa554v pages 1-2, de2024structuralinsightinto pages 1-3)
- UHRF1-dependent histone and replication-factor ubiquitination provides a replication-coupled “handoff” mechanism that ensures DNMT1 acts on hemimethylated DNA and avoids inappropriate methylation. (cuesta2024roleofuhrf1 pages 38-42, cuesta2024roleofuhrf1 pages 46-50)
- Maintenance methylation appears to include a fast (minutes) and slow (hours) phase, implying DNMT1 function is integrated with chromatin assembly dynamics and may not be completed immediately at the fork in all genomic contexts. (cuesta2024roleofuhrf1 pages 42-46)
- In therapeutic contexts, DNMT1 serves as both an epigenetic enzyme and a chemical vulnerability because substrate-analogue drugs can trap DNMT1 as toxic DPCs, making DPC repair and metabolism key determinants of efficacy. (carnie2024decitabinecytotoxicityis pages 1-2)

7) Summary table of evidence

Aspect	Key Mechanisms & Quantitative Findings	Key Recent Sources (2023–2024)
Enzymatic Reaction & Substrate	Catalyzes transfer of methyl group from SAM to cytosine C5 in CpG dinucleotides. High preference for hemimethylated DNA (maintenance); poor activity on oxidized forms (hm5C, f5C).	Davletgildeeva & Kuznetsov, Biomolecules (Sep 2024) (davletgildeeva2024theroleof pages 4-5); Cuesta, Unknown (2024) (cuesta2024roleofuhrf1 pages 38-42)
Domain Architecture	1620 aa protein. N-term: DMAP1-binding, RFTS (Replication Foci Targeting Sequence, autoinhibitory), CXXC (binds unmethylated CpG), 2×BAH domains. C-term: Catalytic Methyltransferase domain.	Switzer et al., DNA (Jul 2023) (switzer2023diseaseassociatedmutationa554v pages 1-2); Davletgildeeva & Kuznetsov, Biomolecules (Sep 2024) (davletgildeeva2024theroleof pages 4-5)
Localization & Dynamics	Localizes to replication foci in S-phase (via RFTS) and heterochromatin in G2. Excluded from nucleus in early embryogenesis (passive demethylation).	Prakash, PhD Thesis (Jan 2024) (prakash2024characterizationofdnmt3cmediated pages 35-39); Davletgildeeva & Kuznetsov, Biomolecules (Sep 2024) (davletgildeeva2024theroleof pages 4-5)
Recruitment & Complexes	Recruited by UHRF1 (SRA binds hemi-mCpG). Dual mono-ubiquitination of H3 (K18/K23) and PAF15 by UHRF1 is essential for DNMT1 binding/activation. Complex includes PCNA, USP7 (regulates stability).	Cuesta, Unknown (2024) (cuesta2024roleofuhrf1 pages 42-46, cuesta2024roleofuhrf1 pages 38-42); Miyashita et al., eLife (May 2023) (miyashita2023theterminationof pages 27-28)
Allostery & Autoinhibition	RFTS domain occupies catalytic pocket in apo state (autoinhibition). Binding of H3Ub2 and/or hemi-mDNA displaces RFTS. Mutations (e.g., A554V) weaken RFTS inhibition $\rightarrow$ ~8-fold higher DNA binding & hyperactivity.	De et al., PLOS ONE (Sep 2024) (de2024structuralinsightinto pages 12-13, de2024structuralinsightinto pages 1-3); Switzer et al., DNA (Jul 2023) (switzer2023diseaseassociatedmutationa554v pages 1-2, switzer2023diseaseassociatedmutationa554v pages 11-12)
DNA Repair & DPCs	Trapped by 5-aza-dC/Decitabine forming DNMT1-DPCs (toxic crosslinks). Repair via SUMOylation $\rightarrow$ Ubiquitylation (TOPORS E3 ligase identified 2024) $\rightarrow$ Proteolysis (SPRTN/Proteasome). Recruited to DSBs via PCNA.	Carnie et al., EMBO J (May 2024) (carnie2024decitabinecytotoxicityis pages 1-2); Carnie et al., Nat Cell Biol (Apr 2024) (carnie2024transcriptioncoupledrepairof pages 1-2); Marco et al., Cancers (Oct 2023) (marco2023histoneanddna pages 5-7)
Quantitative Kinetics	Maintenance rates: >50% of hemi-mCpGs restored within ~4 min of fork passage (fast phase); full restoration takes ~10 h (slow phase). Loss effects: 2–4 days depletion $\rightarrow$ massive demethylation & G1 arrest.	Cuesta, Unknown (2024) (cuesta2024roleofuhrf1 pages 42-46); Scelfo et al., J Cell Biol (Feb 2024) (scelfo2024tunablednmt1degradation pages 3-3); Martino et al., Cell Mol Life Sci (Dec 2024) (martino2024dnmt1prolongedabsence pages 1-2)
Clinical: Drugs & Biomarkers	Drugs: Decitabine, Azacitidine, Aza-T-dCyd (novel, IC50 0.048 µM). Response: ~30–50% in MDS/AML. Resistance: Associated with DCTD loss (prevents 5-aza-dUMP) or DNMT1 deletion (~9% colon cancers; IC50 >10 µM).	Carnie et al., EMBO J (May 2024) (carnie2024decitabinecytotoxicityis pages 1-2); Laranjeira et al., Sci Rep (Apr 2023) (laranjeira2023dnadamagedemethylation pages 1-2); Laranjeira et al., Diseases (Jul 2024) (laranjeira2024upregulationoftet2 pages 1-2)

Table: This table synthesizes recent experimental evidence characterizing human DNMT1, including its catalytic mechanism, domain-mediated autoinhibition, role in DNA damage repair via protein crosslinks (DPCs), and quantitative kinetics of maintenance methylation and drug response.

8) Visual evidence: DNMT1 domain organization and autoinhibitory RFTS conformation

A figure from Switzer et al. (2023, Jul; https://doi.org/10.3390/dna3030010) provides a domain map and structural depiction of DNMT1 autoinhibition (RFTS bound to the catalytic domain), consistent with modern models for allosteric activation by partner interactions and histone ubiquitination. (switzer2023diseaseassociatedmutationa554v media 906136d4)

Key recent references (publication date + URL)

De et al. (Sep 2024) PLOS ONE: “Structural insight into the DNMT1 reaction cycle by cryo-electron microscopy.” https://doi.org/10.1371/journal.pone.0307850 (de2024structuralinsightinto pages 1-3)
Davletgildeeva & Kuznetsov (Sep 2024) Biomolecules: “The Role of DNMT Methyltransferases and TET Dioxygenases in the Maintenance of the DNA Methylation Level.” https://doi.org/10.3390/biom14091117 (davletgildeeva2024theroleof pages 4-5)
Carnie et al. (May 2024) The EMBO Journal: “Decitabine cytotoxicity is promoted by dCMP deaminase DCTD and mitigated by SUMO-dependent E3 ligase TOPORS.” https://doi.org/10.1038/s44318-024-00108-2 (carnie2024decitabinecytotoxicityis pages 1-2)
Carnie et al. (Apr 2024) Nature Cell Biology: “Transcription-coupled repair of DNA–protein cross-links depends on CSA and CSB.” https://doi.org/10.1038/s41556-024-01391-1 (carnie2024transcriptioncoupledrepairof pages 1-2)
Scelfo et al. (Feb 2024) Journal of Cell Biology: “Tunable DNMT1 degradation reveals DNMT1/DNMT3B synergy in DNA methylation and genome organization.” https://doi.org/10.1083/jcb.202307026 (scelfo2024tunablednmt1degradation pages 3-3)
Martino et al. (Dec 2024) Cellular and Molecular Life Sciences: “DNMT1 prolonged absence is a tunable cellular stress…” https://doi.org/10.1007/s00018-024-05547-y (martino2024dnmt1prolongedabsence pages 1-2)
Ngan et al. (May 2023) eLife: “Activity-based CRISPR scanning uncovers allostery in DNA methylation maintenance machinery.” https://doi.org/10.7554/elife.80640 (ngan2023activitybasedcrisprscanning pages 9-10)
Switzer et al. (Jul 2023) DNA: “Disease-Associated Mutation A554V Disrupts Normal Autoinhibition of DNMT1.” https://doi.org/10.3390/dna3030010 (switzer2023diseaseassociatedmutationa554v pages 1-2)
Laranjeira et al. (Apr 2023) Scientific Reports: “DNA damage, demethylation and anticancer activity of DNA methyltransferase inhibitors.” https://doi.org/10.1038/s41598-023-32509-4 (laranjeira2023dnadamagedemethylation pages 1-2)
Miyashita et al. (May 2023) eLife: “The termination of UHRF1-dependent PAF15 ubiquitin signaling is regulated by USP7 and ATAD5.” https://doi.org/10.7554/elife.79013 (miyashita2023theterminationof pages 27-28)

References

(switzer2023diseaseassociatedmutationa554v pages 1-2): Rebecca L. Switzer, Zach J. Hartman, Geoffrey R. Hewett, and Clara F. Carroll. Disease-associated mutation a554v disrupts normal autoinhibition of dnmt1. DNA, 3:119-133, Jul 2023. URL: https://doi.org/10.3390/dna3030010, doi:10.3390/dna3030010. This article has 2 citations.
(laranjeira2023dnadamagedemethylation pages 1-2): Angelo B. A. Laranjeira, Melinda G. Hollingshead, Dat Nguyen, Robert J. Kinders, James H. Doroshow, and Sherry X. Yang. Dna damage, demethylation and anticancer activity of dna methyltransferase (dnmt) inhibitors. Scientific Reports, Apr 2023. URL: https://doi.org/10.1038/s41598-023-32509-4, doi:10.1038/s41598-023-32509-4. This article has 73 citations and is from a peer-reviewed journal.
(davletgildeeva2024theroleof pages 4-5): Anastasiia T. Davletgildeeva and Nikita A. Kuznetsov. The role of dnmt methyltransferases and tet dioxygenases in the maintenance of the dna methylation level. Biomolecules, 14:1117, Sep 2024. URL: https://doi.org/10.3390/biom14091117, doi:10.3390/biom14091117. This article has 44 citations.
(cuesta2024roleofuhrf1 pages 38-42): C Fernandez Cuesta. Role of uhrf1 and histone h3 ubiquitination in chromatin re-establishment during dna replication. Unknown journal, 2024.
(de2024structuralinsightinto pages 1-3): Inessa De, Jonas Weidenhausen, Nestor Concha, and Christoph W. Müller. Structural insight into the dnmt1 reaction cycle by cryo-electron microscopy. PLOS ONE, 19:e0307850, Sep 2024. URL: https://doi.org/10.1371/journal.pone.0307850, doi:10.1371/journal.pone.0307850. This article has 3 citations and is from a peer-reviewed journal.
(prakash2024characterizationofdnmt3cmediated pages 35-39): Characterization of DNMT3C-mediated inactivation of active transposons in mouse This article has 0 citations and is from a peer-reviewed journal.
(switzer2023diseaseassociatedmutationa554v media 906136d4): Rebecca L. Switzer, Zach J. Hartman, Geoffrey R. Hewett, and Clara F. Carroll. Disease-associated mutation a554v disrupts normal autoinhibition of dnmt1. DNA, 3:119-133, Jul 2023. URL: https://doi.org/10.3390/dna3030010, doi:10.3390/dna3030010. This article has 2 citations.
(cuesta2024roleofuhrf1 pages 42-46): C Fernandez Cuesta. Role of uhrf1 and histone h3 ubiquitination in chromatin re-establishment during dna replication. Unknown journal, 2024.
(cuesta2024roleofuhrf1 pages 46-50): C Fernandez Cuesta. Role of uhrf1 and histone h3 ubiquitination in chromatin re-establishment during dna replication. Unknown journal, 2024.
(de2024structuralinsightinto pages 10-12): Inessa De, Jonas Weidenhausen, Nestor Concha, and Christoph W. Müller. Structural insight into the dnmt1 reaction cycle by cryo-electron microscopy. PLOS ONE, 19:e0307850, Sep 2024. URL: https://doi.org/10.1371/journal.pone.0307850, doi:10.1371/journal.pone.0307850. This article has 3 citations and is from a peer-reviewed journal.
(de2024structuralinsightinto pages 12-13): Inessa De, Jonas Weidenhausen, Nestor Concha, and Christoph W. Müller. Structural insight into the dnmt1 reaction cycle by cryo-electron microscopy. PLOS ONE, 19:e0307850, Sep 2024. URL: https://doi.org/10.1371/journal.pone.0307850, doi:10.1371/journal.pone.0307850. This article has 3 citations and is from a peer-reviewed journal.
(ngan2023activitybasedcrisprscanning pages 9-10): Kevin C. Ngan, Samuel M. Hoenig, Pallavi M. Gosavi, David A. Tanner, Nicholas Z. Lue, Emma M. Garcia, Ceejay Lee, and Brian B. Liau. Activity-based crispr scanning uncovers allostery in dna methylation maintenance machinery. eLife, May 2023. URL: https://doi.org/10.7554/elife.80640, doi:10.7554/elife.80640. This article has 21 citations and is from a domain leading peer-reviewed journal.
(switzer2023diseaseassociatedmutationa554v pages 11-12): Rebecca L. Switzer, Zach J. Hartman, Geoffrey R. Hewett, and Clara F. Carroll. Disease-associated mutation a554v disrupts normal autoinhibition of dnmt1. DNA, 3:119-133, Jul 2023. URL: https://doi.org/10.3390/dna3030010, doi:10.3390/dna3030010. This article has 2 citations.
(martino2024dnmt1prolongedabsence pages 1-2): Salvatore Martino, Serena Gargano, Pietro Salvatore Carollo, Aldo Di Leonardo, and Viviana Barra. Dnmt1 prolonged absence is a tunable cellular stress that triggers cell proliferation arrest to protect from major dna methylation loss. Cellular and Molecular Life Sciences: CMLS, Dec 2024. URL: https://doi.org/10.1007/s00018-024-05547-y, doi:10.1007/s00018-024-05547-y. This article has 6 citations.
(scelfo2024tunablednmt1degradation pages 3-3): Andrea Scelfo, Viviana Barra, Nezar Abdennur, George Spracklin, Florence Busato, Catalina Salinas-Luypaert, Elena Bonaiti, Guillaume Velasco, Frédéric Bonhomme, Anna Chipont, Andréa E. Tijhuis, Diana C.J. Spierings, Coralie Guérin, Paola Arimondo, Claire Francastel, Floris Foijer, Jӧrg Tost, Leonid Mirny, and Daniele Fachinetti. Tunable dnmt1 degradation reveals dnmt1/dnmt3b synergy in dna methylation and genome organization. The Journal of Cell Biology, Feb 2024. URL: https://doi.org/10.1083/jcb.202307026, doi:10.1083/jcb.202307026. This article has 25 citations.
(marco2023histoneanddna pages 5-7): Katia De Marco, Paola Sanese, Cristiano Simone, and Valentina Grossi. Histone and dna methylation as epigenetic regulators of dna damage repair in gastric cancer and emerging therapeutic opportunities. Cancers, 15:4976, Oct 2023. URL: https://doi.org/10.3390/cancers15204976, doi:10.3390/cancers15204976. This article has 14 citations.
(silvahurtado2024emergingapplicationsof pages 1-2): Thenzing J Silva-Hurtado, Julio F. Inocencio, and Raymund L. Yong. Emerging applications of hypomethylating agents in the treatment of glioblastoma (review). Molecular and Clinical Oncology, Jun 2024. URL: https://doi.org/10.3892/mco.2024.2757, doi:10.3892/mco.2024.2757. This article has 5 citations.
(gallimore2023therapeuticapplicationsof pages 2-4): Fallon Gallimore and Tamer E. Fandy. Therapeutic applications of azanucleoside analogs as dna demethylating agents. Epigenomes, 7:12, Jul 2023. URL: https://doi.org/10.3390/epigenomes7030012, doi:10.3390/epigenomes7030012. This article has 9 citations.
(carnie2024decitabinecytotoxicityis pages 1-2): Christopher J. Carnie, Maximilian J. Götz, Chloe S. Palma-Chaundler, P. Weickert, Amy R. Wanders, Almudena Serrano-Benitez, Hao-Yi Li, Vipul Gupta, Samah W. Awwad, Christian J Blum, Matylda Sczaniecka-Clift, Jacqueline Cordes, Guido Zagnoli-Vieira, Giuseppina D'Alessandro, Sean L. Richards, Nadia Gueorguieva, Simon Lam, Petra Beli, Julian Stingele, and S. P. Jackson. Decitabine cytotoxicity is promoted by dcmp deaminase dctd and mitigated by sumo-dependent e3 ligase topors. The EMBO Journal, 43:2397-2423, May 2024. URL: https://doi.org/10.1038/s44318-024-00108-2, doi:10.1038/s44318-024-00108-2. This article has 33 citations.
(carnie2024transcriptioncoupledrepairof pages 1-2): Christopher J. Carnie, Aleida C. Acampora, Aldo S. Bader, Chimeg Erdenebat, Shubo Zhao, Elnatan Bitensky, Diana van den Heuvel, Avital Parnas, Vipul Gupta, Giuseppina D’Alessandro, Matylda Sczaniecka-Clift, Pedro Weickert, Fatih Aygenli, Maximilian J. Götz, Jacqueline Cordes, Isabel Esain-Garcia, Larry Melidis, Annelotte P. Wondergem, Simon Lam, Maria S. Robles, Shankar Balasubramanian, Sheera Adar, Martijn S. Luijsterburg, Stephen P. Jackson, and Julian Stingele. Transcription-coupled repair of dna–protein cross-links depends on csa and csb. Nature Cell Biology, 26:797-810, Apr 2024. URL: https://doi.org/10.1038/s41556-024-01391-1, doi:10.1038/s41556-024-01391-1. This article has 54 citations and is from a highest quality peer-reviewed journal.
(laranjeira2024upregulationoftet2 pages 1-2): Angelo B. A. Laranjeira, Dat Nguyen, Lorraine C. Pelosof, James H. Doroshow, and Sherry X. Yang. Upregulation of tet2 and resistance to dna methyltransferase (dnmt) inhibitors in dnmt1-deleted cancer cells. Diseases, 12:163, Jul 2024. URL: https://doi.org/10.3390/diseases12070163, doi:10.3390/diseases12070163. This article has 10 citations.
(miyashita2023theterminationof pages 27-28): Ryota Miyashita, Atsuya Nishiyama, Yoshie Chiba, Satomi Kori, Norie Kato, Chieko Konishi, Soichiro Kumamoto, Hiroko Kozuka-Hata, Masaaki Oyama, Yoshitaka Kawasoe, Toshiki Tsurimoto, Tatsuro S Takahashi, Kyohei Arita, and Makoto Nakanishi. The termination of uhrf1-dependent paf15 ubiquitin signaling is regulated by usp7 and atad5. eLife, May 2023. URL: https://doi.org/10.7554/elife.79013, doi:10.7554/elife.79013. This article has 14 citations and is from a domain leading peer-reviewed journal.

Citations

davletgildeeva2024theroleof pages 4-5
de2024structuralinsightinto pages 1-3
de2024structuralinsightinto pages 12-13
de2024structuralinsightinto pages 10-12
ngan2023activitybasedcrisprscanning pages 9-10
marco2023histoneanddna pages 5-7
silvahurtado2024emergingapplicationsof pages 1-2
carnie2024decitabinecytotoxicityis pages 1-2
carnie2024transcriptioncoupledrepairof pages 1-2
laranjeira2023dnadamagedemethylation pages 1-2
miyashita2023theterminationof pages 27-28
gallimore2023therapeuticapplicationsof pages 2-4
https://doi.org/10.3390/dna3030010
https://doi.org/10.1371/journal.pone.0307850
https://doi.org/10.3390/biom14091117
https://doi.org/10.1038/s44318-024-00108-2
https://doi.org/10.1038/s41556-024-01391-1
https://doi.org/10.1083/jcb.202307026
https://doi.org/10.1007/s00018-024-05547-y
https://doi.org/10.7554/elife.80640
https://doi.org/10.1038/s41598-023-32509-4
https://doi.org/10.7554/elife.79013
https://doi.org/10.3390/dna3030010,
https://doi.org/10.1038/s41598-023-32509-4,
https://doi.org/10.3390/biom14091117,
https://doi.org/10.1371/journal.pone.0307850,
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https://doi.org/10.1007/s00018-024-05547-y,
https://doi.org/10.1083/jcb.202307026,
https://doi.org/10.3390/cancers15204976,
https://doi.org/10.3892/mco.2024.2757,
https://doi.org/10.3390/epigenomes7030012,
https://doi.org/10.1038/s44318-024-00108-2,
https://doi.org/10.1038/s41556-024-01391-1,
https://doi.org/10.3390/diseases12070163,
https://doi.org/10.7554/elife.79013,

DNMT1 (DNA Methyltransferase 1) - Deep Research

(DNMT1-deep-research.md)

DNMT1 (DNA Methyltransferase 1) - Deep Research

Overview

DNMT1 (DNA methyltransferase 1) is the predominant mammalian DNA methyltransferase responsible for maintaining genomic DNA methylation patterns during cell division. It is a large, multidomain protein of 1616 amino acids (UniProt: P26358) with a molecular weight of approximately 183-190 kDa when accounting for post-translational modifications. DNMT1 is essential for epigenetic inheritance, playing crucial roles in gene regulation, genomic stability, X-chromosome inactivation, and genomic imprinting.

Gene and Protein Structure

Basic Information

Gene location: Human chromosome 19p13.2
Protein size: 1616 amino acids
Molecular weight: ~183 kDa (theoretical), 185-190 kDa (observed on SDS-PAGE due to extensive post-translational modifications)
UniProt ID: P26358

Domain Architecture

DNMT1 exhibits a complex three-layer architecture revealed by crystal structures (PDB: multiple structures including 5WVO, 7XI9):

N-terminal Regulatory Region (aa 1-1100)
RFTS Domain (Replication Foci Targeting Sequence): Recognizes H3K9me3 marks and H3 ubiquitylation; acts as an autoinhibitory domain that can occlude the catalytic site
CXXC Domain: Zinc finger domain that specifically recognizes unmethylated CpG dinucleotides
BAH Domains (Bromo-Adjacent Homology): Two tandem domains (BAH1 and BAH2); BAH1 recognizes H4K20me3 marks
Linker Region (aa 1109-1120)
Contains Gly-Lys linker segment
Autoinhibitory linker positioned in catalytic cleft when binding unmethylated CpG
C-terminal Catalytic Domain (aa 1121-1616)
Contains 10 conserved motifs shared with prokaryotic methyltransferases
Active site with conserved FxGxG motif for S-adenosyl-L-methionine (SAM) binding
Catalytic cysteine residue (Cys1226) essential for mechanism

Enzymatic Mechanism

Catalytic Mechanism

DNMT1 catalyzes methylation through a well-characterized three-step mechanism:

Base Flipping: Target cytosine is extracted from DNA double helix and inserted into catalytic pocket
Nucleophilic Attack: Cys1226 attacks C6 position of cytosine, forming covalent intermediate
Methyl Transfer: SAM donates methyl group to C5 position of cytosine; β-elimination releases 5-methylcytosine

The methyl transfer step is rate-limiting, occurring via a loose SN2 mechanism distinguishing DNMT1 from other methyltransferases.

Substrate Specificity

Hemimethylated CpG Preference: DNMT1 shows strong preference for hemimethylated CpG sites with 2-fold higher specific activity compared to unmethylated sites PMID:17965604. This specificity is critical for its maintenance methyltransferase function during DNA replication.

UHRF1-mediated Activation: Activity is enhanced ~5-fold by interaction with UHRF1 PMID:23186163. UHRF1 binding induces conformational changes that relieve autoinhibition and promote catalytic activity.

Processivity and Linear Diffusion: DNMT1 exhibits distributive methylation behavior on long DNA substrates but shows enhanced processivity on hemimethylated CpG-rich regions PMID:17965604. The enzyme can scan DNA through both sliding and hopping mechanisms to locate target sites.

SAM Binding and Allosteric Effects: S-adenosyl-L-methionine binding exhibits positive cooperativity and allosterically enhances DNA binding affinity PMID:17965604. This coupling ensures efficient methylation when methyl donor is abundant.

Protein Interactions and Regulation

Post-Translational Modifications

Phosphorylation

Ser143: Phosphorylated by AKT1, creates stability switch with Lys142 methylation
Ser154: Phosphorylated by CDK1/2/5, enhances activity and stability
Ser410/414: GSK3β sites, affect protein accumulation

Acetylation

Destabilizing acetylation by Tip60
Stabilizing deacetylation by HDAC1 and SIRT1
KG linker acetylation impairs USP7 interaction

Methylation

Lys142 methylation by SET7 promotes degradation
Creates mutually exclusive switch with Ser143 phosphorylation

Ubiquitination

UHRF1-mediated ubiquitination for degradation
USP7 (HAUSP) deubiquitination for stabilization

Expression and Localization

Tissue Distribution

Ubiquitously expressed with highest levels in:
Testis (spermatogenesis stages except pachytene)
Placenta
Spleen
Bone marrow
Peripheral blood leukocytes
Nuclear localization in proliferating cells
Cell cycle-dependent expression (peaks in S-phase)

Developmental Expression

High in undifferentiated/proliferating cells
Cytoplasmic in mature oocytes
Nuclear translocation during embryogenesis
Required for stem cell maintenance in humans (not mice)

Subcellular Dynamics

S-phase: Accumulates at replication foci via PCNA interaction
G2/M phases: Associates with constitutive heterochromatin
Dynamic exchange at replication sites
Continuous chromatin binding throughout cell cycle

Isoforms and Splice Variants

Major Isoforms

DNMT1s (Somatic form)
1616 amino acids
Predominant in somatic tissues
Nuclear localization
DNMT1o (Oocyte-specific form)
Alternative promoter usage (6 kb upstream)
Lacks first 118 amino acids
Cytoplasmic storage in oocytes
Nuclear translocation at 8-cell stage
Critical for maintaining imprints
DNMT1b (Minor splice variant)
Contains 16 additional amino acids from Alu repeat
2-5% of total DNMT1 protein
Functional methyltransferase

DNMT Family Relationships

Mammalian DNMT Family

DNMT1: Maintenance methyltransferase
DNMT2: RNA methyltransferase (not DNA)
DNMT3A/3B: De novo methyltransferases
DNMT3L: Catalytically inactive, regulatory function

Evolutionary Conservation

DNMT1 and DNMT3A present in common metazoan ancestor
DNMT3B arose near tetrapod origin
DNMT3L evolved from DNMT3A in eutherian mammals
Lineage-specific duplications in marsupials

Functional Specialization

DNMT1: CpG maintenance during replication
DNMT3A/B: De novo methylation establishment
Cooperative function for genomic methylation patterns

Biological Functions

DNA Methylation Maintenance

Preserves methylation patterns through cell division
Essential for epigenetic inheritance
Targets hemimethylated CpG sites post-replication

Genomic Imprinting

DNMT1o maintains imprints during early embryogenesis
Critical at imprinting control regions
Loss causes imprinting defects and developmental abnormalities

X-Chromosome Inactivation

Required for maintaining inactive X chromosome
DNMT1o links XCI to autosomal imprinting
Disruption affects placental development in females

Genomic Stability

Silences repetitive elements (LINE, SINE, satellites)
Prevents transposon activation
Maintains centromeric stability

Gene Regulation

Silences tissue-specific genes
Maintains heterochromatin
Regulates developmental gene expression

Disease Associations

Hereditary Disorders

HSAN1E (Hereditary Sensory and Autonomic Neuropathy Type 1E)
Mutations in RFTS domain (exon 20)
Sensory neuropathy, hearing loss, dementia
Onset typically in teens/early 20s
ADCA-DN (Autosomal Dominant Cerebellar Ataxia, Deafness, and Narcolepsy)
Mutations in exon 21
Cerebellar ataxia, narcolepsy/cataplexy
Progressive neurodegeneration

Cancer

Overexpression in Tumors
Commonly upregulated in various cancers
Associated with CpG Island Methylator Phenotype (CIMP)
Silences tumor suppressor genes
Specific Cancer Types
Colorectal cancer (CIMP phenotype)
Gastric cancer
Gliomas
Pancreatic, breast, bladder, lung cancers
Prognostic Significance
High expression correlates with poor differentiation
Associated with hypermethylation of multiple CpG islands
Potential therapeutic target

Other Conditions

Beckwith-Wiedemann syndrome (imprinting disorders)
ICF syndrome (though primarily DNMT3B-related)
Chemotherapy-associated cognitive impairment

Therapeutic Targeting

FDA-Approved DNMT Inhibitors

Azacitidine (Vidaza)
Approved for myelodysplastic syndrome (MDS)
Nucleoside analog incorporated into DNA
Forms covalent complex with DNMTs
Oral form (Onureg) approved for AML maintenance
Decitabine (Dacogen)
Derivative of azacitidine
Approved for MDS
Lower doses for demethylation
Higher doses cause cytotoxicity

Investigational Compounds

Guadecitabine (SGI-110): Second-generation, improved stability
Non-nucleoside inhibitors in development
Combination therapies with venetoclax showing promise

Clinical Applications

Hematologic Malignancies: Response rates of 35-60% in MDS/AML PMID:27924838. Particularly effective in elderly patients who cannot tolerate intensive chemotherapy.

Combination Therapy Successes: While most combination attempts have failed in randomized clinical trials, venetoclax combinations represent a breakthrough PMID:27924838. These combinations show significantly improved overall survival in AML.

Solid Tumor Challenges: Application in solid tumors remains challenging due to low response rates and lack of optimal combination strategies PMID:27924838. However, low-dose decitabine combined with cytotoxic drugs has shown encouraging results with response rates up to 60% in select solid tumors.

Biomarker-guided Therapy: Recent 2023 research identified DNMT1 expression levels and RAS/MEK/ERK pathway activity as predictive biomarkers for 5-azacytidine sensitivity in gastric cancer PMID:37702447. This represents progress toward personalized treatment approaches.

Resistance Mechanisms: DNMT1 gene deletion/disruption markedly attenuates cytotoxicity of decitabine, azacitidine, and other DNMT inhibitors PMID:36995181, highlighting the importance of maintaining target expression for therapeutic efficacy.

Species Differences and Model Systems

Mouse vs Human ESCs

Mouse: Can survive without DNA methylation
Human: DNMT1 deletion causes rapid cell death
Reflects different pluripotent states
Important for disease modeling

Knockout Phenotypes

Mouse DNMT1 KO: Embryonic lethal, imprinting defects
Human ESC KO: Immediate lethality without rescue
Conditional KO: Tissue-specific effects

Regulatory Mechanisms

Autoinhibition

RFTS domain occludes active site
CXXC-BAH1 linker blocks catalytic cleft
Released upon binding appropriate substrate

Allosteric Regulation

UHRF1 binding causes conformational changes
Histone modifications influence activity
Domain rearrangements control access to DNA

Cell Cycle Regulation

Expression peaks in S-phase
CDK phosphorylation enhances activity
Degradation in G0/G1 phases

Current Research Directions

Structural Biology

Complete structures with all domains
Dynamics of domain movements
Substrate recognition mechanisms

Therapeutic Development

Selective DNMT1 inhibitors
Combination therapies
Overcoming resistance mechanisms

Basic Biology

Single-cell methylation dynamics and heterogeneity in maintenance methylation
Role in cellular plasticity and epigenetic reprogramming
Interaction with other epigenetic modifiers (chromatin remodeling complexes, histone modifying enzymes)
Mechanistic understanding of recruitment to repetitive elements and heterochromatin

Key Recent Discoveries (2020-2024)

Structural and Mechanistic Insights

H3 Ubiquitination Activation Mechanism PMID:36271982: Recent molecular dynamics simulations have elucidated how histone H3 ubiquitination triggers DNMT1 activation through conformational changes in the RFTS domain.
DNMT1-UHRF1-PCNA Complex Dynamics PMID:36995181: 2023 studies revealed the robustness of the replication-coupled methylation machinery even under stress conditions.
Allosteric Regulation Mechanisms: Crystal structures (PDB: 5WVO, 7XI9) revealed dual autoinhibitory mechanisms involving both RFTS and CXXC domains, with large domain rearrangements controlling catalytic activity through sophisticated allosteric mechanisms.

Therapeutic and Clinical Advances

Gastric Cancer Therapeutic Targeting PMID:37702447: 2023 research identified RAS/MEK/ERK pathway modulation of DNMT1 as a determinant of therapeutic response.
Venetoclax Combination Therapy: Clinical trials combining hypomethylating agents with venetoclax showed improved outcomes in AML/MDS, representing one of the few successful combination strategies.
Novel Non-nucleoside Inhibitors: Development of GSK-3484862, a non-covalent DNMT1 inhibitor with improved pharmacokinetic properties compared to nucleoside analogs.

Disease Mechanisms

Neurodegeneration and Proteostasis PMID:32760389: Understanding of DNMT1's role in protein quality control and neurodegeneration.
Myocardial Fibrosis Regulation PMID:37702447: 2023 discovery of DNMT1's role in cardiac pathology through microRNA regulation.

Methodological Advances

Single-cell Methylation Dynamics: Development of techniques to study DNMT1 activity at single-cell resolution, revealing heterogeneity in maintenance methylation.
Epigenetic Clocks and Aging: DNMT1's central role in age-related methylation changes and potential biomarker applications for aging and disease.

Clinical Significance Summary

DNMT1 represents a critical epigenetic regulator with far-reaching implications for human health:
- Essential for normal development and differentiation
- Dysregulation causes neurological disorders and cancer
- Validated therapeutic target with FDA-approved drugs
- Biomarker for cancer prognosis and treatment response
- Central to understanding epigenetic inheritance

Future Perspectives

The study of DNMT1 continues to reveal fundamental principles of epigenetic regulation while offering therapeutic opportunities. Key areas for future research include:
- Development of selective, non-toxic inhibitors
- Understanding tissue-specific functions
- Elucidating interactions with emerging epigenetic regulators
- Exploring role in cellular reprogramming and regenerative medicine
- Developing biomarkers for personalized therapy

The central role of DNMT1 in maintaining genomic methylation patterns makes it both a fundamental biological regulator and a prime therapeutic target for diseases characterized by aberrant DNA methylation.

Experimental Methods and Validation

Key Experimental Approaches

Biochemical Assays:
- Methyltransferase activity assays using radiolabeled SAM or HPLC-based methods
- Isothermal titration calorimetry for protein-protein and protein-DNA interactions (e.g., DNMT1 PIP box-PCNA: Kd = 1.00 ± 0.05 μM)
- Surface plasmon resonance for real-time binding kinetics

Structural Studies:
- X-ray crystallography revealing multiple conformational states (PDB: 4WXX, 5WVO, 7XI9)
- Cryo-electron microscopy for large complex structures
- Cross-linking mass spectrometry for domain interactions in solution

Cellular and Molecular Biology:
- ChIP-seq and bisulfite sequencing for genome-wide methylation mapping
- FRAP (Fluorescence Recovery After Photobleaching) for protein dynamics at replication foci
- Single-cell methylation analysis revealing heterogeneity in maintenance efficiency

Functional Genomics:
- CRISPR/Cas9 knockout and rescue experiments
- Domain deletion mutants to dissect functional contributions
- Complementation assays in methylation-deficient cell lines

Critical Validation Considerations

Antibody Specificity: DNMT1 antibodies must be validated for specificity, as cross-reactivity with DNMT3 family members can occur. Western blots should include knockdown controls and size markers (full-length DNMT1: ~190 kDa including PTMs).

Methylation Detection: Bisulfite-independent methods (e.g., methylation-sensitive restriction enzymes, 5mC immunoprecipitation) should complement bisulfite sequencing to avoid conversion artifacts.

Commonly Over-annotated Functions and Cautions

Over-annotations to Avoid

General "DNA binding": While DNMT1 binds DNA, this is non-specific. Focus on "hemimethylated DNA binding" or "CpG dinucleotide binding" which reflect specific functional interactions.
Broad "transcriptional regulation": DNMT1's transcriptional effects are primarily indirect through DNA methylation. Direct transcriptional regulation roles should be distinguished from methylation-mediated effects.
Protein binding without functional context: Many proteins interact with DNMT1 in proteomics studies, but only functionally validated interactions (UHRF1, PCNA, histones, USP7) should be considered core functions.
Developmental processes without mechanistic basis: While DNMT1 is important in development, specific process annotations should be supported by mechanistic understanding of which genes/pathways are methylated.

Core vs. Peripheral Functions

Core Functions (well-validated):
- DNA (cytosine-5)-methyltransferase activity
- Hemimethylated CpG site recognition and binding
- Maintenance of genomic methylation during replication
- Genomic imprinting maintenance
- X-chromosome inactivation maintenance
- Repetitive element silencing

Peripheral/Contextual Functions (cell-type or condition-specific):
- Tissue-specific gene silencing programs
- Stress response methylation changes
- Age-related methylation drift
- Cancer-specific hypermethylation patterns

Questionable/Over-annotations:
- Direct roles in apoptosis (likely indirect through target gene methylation)
- DNA repair activities (may be recruitment to repair sites, not repair activity per se)
- Direct cell cycle regulation (expression is cell cycle-regulated, but direct regulatory roles unclear)

📄 View Raw YAML

id: P26358
gene_symbol: DNMT1
aliases:
- DNMT
- MCMT
- CXXC9
- AIM
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: DNMT1 is the predominant mammalian maintenance DNA methyltransferase responsible for preserving CpG methylation patterns during DNA replication. It plays essential roles in genomic imprinting, X-chromosome inactivation, heterochromatin formation, and silencing of repetitive elements. The protein contains multiple regulatory domains including RFTS, CXXC, BAH domains and a C-terminal catalytic domain that uses SAM as methyl donor to methylate cytosine residues in CpG dinucleotides, with 2-fold preference for hemimethylated sites.
existing_annotations:
- term:
    id: GO:0003886
    label: DNA (cytosine-5-)-methyltransferase activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: This IBA annotation correctly identifies DNMT1 as having DNA (cytosine-5)-methyltransferase activity. This is the core catalytic function of DNMT1, well-established through extensive biochemical studies showing it methylates cytosine at the 5-position using S-adenosyl-L-methionine as methyl donor, with preference for hemimethylated CpG sites.
    action: ACCEPT
    reason: This represents the primary and most fundamental molecular function of DNMT1. Multiple studies confirm DNMT1 catalyzes the methylation of cytosine residues at CpG sites, particularly hemimethylated sites during DNA replication maintenance. The IBA evidence represents phylogenetic analysis supporting this core function.
    supported_by:
    - reference_id: PMID:21745816
      supporting_text: USP7 stimulated both the maintenance and de novo DNA methylation activity of Dnmt1 in vitro
    - reference_id: PMID:18754681
      supporting_text: CXXC domain of human DNMT1 is essential for enzymatic activity
    - reference_id: file:human/DNMT1/DNMT1-deep-research.md
      supporting_text: See deep research file for comprehensive analysis
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: DNMT1 is primarily nuclear localized, where it carries out DNA methylation during replication and associates with heterochromatin. Multiple studies confirm nuclear localization with specific enrichment at replication foci during S-phase and pericentric heterochromatin.
    action: ACCEPT
    reason: Nuclear localization is well-established for DNMT1. The protein functions in the nucleus where DNA replication and chromatin organization occur. IBA phylogenetic evidence supports this conserved cellular compartmentalization across species.
    supported_by:
    - reference_id: PMID:8940105
      supporting_text: DNA (cytosine-5)-methyltransferases (EC 2.1.1.37) maintain patterns of methylated cytosine residues in the mammalian genome
    - reference_id: PMID:16791210
      supporting_text: Dynamic proteomics in individual human cells uncovers widespread cell-cycle dependence of nuclear proteins
- term:
    id: GO:0044027
    label: negative regulation of gene expression via chromosomal CpG island methylation
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: DNMT1 negatively regulates gene expression through CpG island methylation, leading to transcriptional silencing. This is a core biological process function of DNMT1, particularly important in cancer where hypermethylation silences tumor suppressor genes and in normal development for silencing tissue-inappropriate genes.
    action: ACCEPT
    reason: This accurately describes a key biological process mediated by DNMT1. CpG island methylation by DNMT1 leads to transcriptional repression through recruitment of methyl-CpG binding proteins and chromatin remodeling complexes. Well-supported by literature showing DNMT1 role in silencing genes via promoter hypermethylation.
    supported_by:
    - reference_id: PMID:24623306
      supporting_text: ZNF304 recruits a corepressor complex that includes the DNA methyltransferase DNMT1, resulting in DNA hypermethylation and transcriptional silencing
    - reference_id: PMID:21745816
      supporting_text: Dnmt1, UHRF1 and USP7 co-localized on silenced, methylated genes in vivo
- term:
    id: GO:0003677
    label: DNA binding
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: DNMT1 binds DNA through multiple domains including the CXXC domain (recognizes unmethylated CpG), catalytic domain (substrate binding), and other regions that interact with chromatin. While DNA binding is necessary for function, this term is quite general and less informative than the specific methyltransferase activity term.
    action: KEEP_AS_NON_CORE
    reason: DNA binding is a prerequisite molecular function for DNMT1 to carry out its methyltransferase activity, but it is a general term that does not capture the specific enzymatic function. The more specific GO:0003886 (DNA cytosine-5-methyltransferase activity) is preferred as the core function. This term represents necessary but non-specific binding activity.
    supported_by:
    - reference_id: PMID:18754681
      supporting_text: CXXC domain of human DNMT1 is essential for enzymatic activity
- term:
    id: GO:0003677
    label: DNA binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: DNA binding annotation for DNMT1.
    action: KEEP_AS_NON_CORE
    reason: DNA binding is accurate but less specific than the DNA methyltransferase activity annotation. Marked as non-core to avoid redundancy with more specific terms.
- term:
    id: GO:0003682
    label: chromatin binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: DNMT1 does bind chromatin through interactions with nucleosomes, histones, and chromatin proteins. It associates with heterochromatin and replication foci. However, this is a somewhat general term that could be made more specific.
    action: ACCEPT
    reason: DNMT1 binding to chromatin is well-documented, including association with nucleosomes, modified histones, and heterochromatin. While general, chromatin binding is a legitimate molecular function distinct from DNA binding alone, as it involves the nucleoprotein complex rather than naked DNA.
    supported_by:
    - reference_id: PMID:21745816
      supporting_text: UHRF1 strongly associates with heterochromatin (15,16) and binds preferentially to hemi-methylated DNA via its SRA domain (13,17–19)
- term:
    id: GO:0003886
    label: DNA (cytosine-5-)-methyltransferase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: DNA (cytosine-5-)-methyltransferase activity annotation for DNMT1.
    action: ACCEPT
    reason: DNA (cytosine-5-)-methyltransferase activity is the core catalytic function of DNMT1. Multiple evidence codes support this annotation.
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: nucleus annotation for DNMT1.
    action: ACCEPT
    reason: Nuclear localization is essential for DNMT1's function in DNA methylation. Multiple evidence codes support this annotation.
- term:
    id: GO:0006346
    label: DNA methylation-dependent constitutive heterochromatin formation
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: DNMT1 contributes to heterochromatin formation through DNA methylation, particularly at repetitive elements and pericentromeric regions. This is a specific and accurate biological process annotation describing an important function of DNMT1 in chromatin organization.
    action: ACCEPT
    reason: DNMT1 plays a well-documented role in heterochromatin formation through DNA methylation. This is particularly important at repetitive sequences, satellite DNA, and pericentromeric regions where DNMT1-mediated methylation helps establish and maintain heterochromatic states essential for genomic stability.
    supported_by:
    - reference_id: PMID:21745816
      supporting_text: UHRF1 strongly associates with heterochromatin
- term:
    id: GO:0008168
    label: methyltransferase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: This is a broad parent term of the more specific DNA (cytosine-5-)-methyltransferase activity. While accurate, it is less informative than the specific terms already annotated.
    action: MODIFY
    reason: This general methyltransferase activity term is too broad. DNMT1 specifically catalyzes DNA cytosine-5-methylation, not general methylation. The more specific GO:0003886 (DNA cytosine-5-methyltransferase activity) is already annotated and preferred.
    proposed_replacement_terms:
    - id: GO:0003886
      label: DNA (cytosine-5-)-methyltransferase activity
- term:
    id: GO:0008270
    label: zinc ion binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: DNMT1 contains a CXXC zinc finger domain that coordinates zinc ions for proper folding and DNA binding function. This molecular function is structurally important for DNMT1 activity.
    action: ACCEPT
    reason: The CXXC domain of DNMT1 is a zinc finger domain that requires zinc coordination for proper folding and function. This zinc finger domain recognizes unmethylated CpG sites and is essential for targeting DNMT1 to appropriate substrates. Zinc binding is a legitimate and important molecular function.
    supported_by:
    - reference_id: PMID:18754681
      supporting_text: CXXC domain of human DNMT1 is essential for enzymatic activity
- term:
    id: GO:0006325
    label: chromatin organization
  evidence_type: IEA
  original_reference_id: GO_REF:0000043
  review:
    summary: DNMT1 contributes to chromatin organization through DNA methylation-mediated recruitment of chromatin remodeling complexes and establishment of heterochromatin. This is a legitimate but broad biological process.
    action: ACCEPT
    reason: DNMT1 plays important roles in chromatin organization by establishing methylation patterns that recruit methyl-CpG binding proteins, chromatin remodeling complexes, and help organize heterochromatin. While broad, this accurately describes an important biological process function of DNMT1.
    supported_by:
    - reference_id: PMID:21745816
      supporting_text: UHRF1 strongly associates with heterochromatin
- term:
    id: GO:0016740
    label: transferase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000043
  review:
    summary: This is an extremely broad parent term for any enzyme that transfers functional groups. While technically correct since DNMT1 transfers methyl groups, it provides no specific information about DNMT1 function.
    action: MODIFY
    reason: This term is far too general and uninformative. DNMT1 specifically transfers methyl groups to DNA cytosines, which is already captured by the more specific GO:0003886 (DNA cytosine-5-methyltransferase activity). The broad transferase activity term should be replaced with the specific methyltransferase activity.
    proposed_replacement_terms:
    - id: GO:0003886
      label: DNA (cytosine-5-)-methyltransferase activity
- term:
    id: GO:0032259
    label: methylation
  evidence_type: IEA
  original_reference_id: GO_REF:0000043
  review:
    summary: This is a very general biological process term for any methylation reaction. While DNMT1 does perform methylation, more specific terms like DNA methylation-related processes are preferred.
    action: MODIFY
    reason: This general methylation term is too broad and uninformative. DNMT1 performs DNA methylation specifically, which is better captured by more specific terms like GO:0141119 (chromosomal DNA methylation maintenance) or GO:0044027 (negative regulation of gene expression via chromosomal CpG island methylation).
    proposed_replacement_terms:
    - id: GO:0141119
      label: chromosomal DNA methylation maintenance following DNA replication
- term:
    id: GO:0046872
    label: metal ion binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000043
  review:
    summary: DNMT1 binds metal ions, particularly zinc in the CXXC domain. However, this is a broad term - the more specific zinc ion binding (GO:0008270) is already annotated and preferred.
    action: MODIFY
    reason: While DNMT1 does bind metal ions (zinc), this general term is less informative than the specific GO:0008270 (zinc ion binding) that is already annotated. The specific term is preferred over the general parent term.
    proposed_replacement_terms:
    - id: GO:0008270
      label: zinc ion binding
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:15161933
  review:
    summary: DNMT1 extensively interacts with numerous proteins including UHRF1, PCNA, USP7, histones, and chromatin factors. However, protein binding is a very general term that does not specify the functional significance of these interactions.
    action: MARK_AS_OVER_ANNOTATED
    reason: While DNMT1 does bind many proteins, this general protein binding term is not informative about DNMT1 specific functions. The numerous IPI annotations with this term represent over-annotation. More specific terms like chromatin binding or enzyme regulator activity would be more informative than generic protein binding.
    additional_reference_ids:
    - PMID:17673620
    - PMID:19450230
    - PMID:21745816
    supported_by:
    - reference_id: PMID:15161933
      supporting_text: 2004 May 25. Comprehensive proteomic analysis of interphase and mitotic 14-3-3-binding proteins.
    - reference_id: PMID:17673620
      supporting_text: Aug 2. UHRF1 plays a role in maintaining DNA methylation in mammalian cells.
    - reference_id: PMID:19450230
      supporting_text: SUMOylation enhances DNA methyltransferase 1 activity.
    - reference_id: PMID:21745816
      supporting_text: Jul 10. The USP7/Dnmt1 complex stimulates the DNA methylation activity of Dnmt1 and regulates the stability of UHRF1.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:16357870
  review:
    summary: Duplicate generic protein binding annotation - shows interaction with EZH2. Multiple IPI annotations exist for the same uninformative term.
    action: MARK_AS_OVER_ANNOTATED
    reason: This represents over-annotation with the same general protein binding term. While this PMID demonstrates DNMT1-EZH2 interaction, the generic GO:0005515 protein binding term provides no functional specificity about this interaction. More specific terms would be more informative.
    supported_by:
    - reference_id: PMID:16357870
      supporting_text: The Polycomb group protein EZH2 directly controls DNA methylation.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:16983096
  review:
    summary: Duplicate generic protein binding annotation. Over-annotation with uninformative term despite showing DNMT3A interaction.
    action: MARK_AS_OVER_ANNOTATED
    reason: Generic protein binding term that does not capture functional significance of DNMT1-DNMT3A interaction. Represents over-annotation where multiple PMIDs are annotated to the same uninformative molecular function term.
    supported_by:
    - reference_id: PMID:16983096
      supporting_text: Recruitment of the de novo DNA methyltransferase Dnmt3a by Kaposi's sarcoma-associated herpesvirus LANA.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:17934516
  review:
    summary: Another duplicate generic protein binding annotation showing DNMT1-ICBP90 interaction. Multiple IPI annotations with this uninformative term represent over-annotation.
    action: MARK_AS_OVER_ANNOTATED
    reason: Generic protein binding term provides no functional specificity about the DNMT1-ICBP90/UHRF1 interaction. While this interaction is functionally important for DNMT1 targeting to hemimethylated sites, the generic GO:0005515 term is uninformative. More specific terms would better capture this regulatory interaction.
    supported_by:
    - reference_id: PMID:17934516
      supporting_text: The interaction of the SRA domain of ICBP90 with a novel domain of DNMT1 is involved in the regulation of VEGF gene expression
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:17972916
  review:
    summary: Generic protein binding annotation showing DNMT1-RIP140 interaction in adipocyte gene silencing context. Multiple uninformative protein binding annotations represent over-annotation.
    action: MARK_AS_OVER_ANNOTATED
    reason: The generic protein binding term does not capture the functional significance of DNMT1-RIP140 interaction in transcriptional silencing of UCP1. While this interaction is functionally relevant, the GO:0005515 term provides no specificity about the regulatory nature of this interaction.
    supported_by:
    - reference_id: PMID:17972916
      supporting_text: Nov 1. RIP140 directs histone and DNA methylation to silence Ucp1 expression in white adipocytes.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:19282482
  review:
    summary: Generic protein binding annotation showing DNMT1-SET7 interaction involved in DNMT1 stability regulation via lysine methylation. Another uninformative generic annotation.
    action: MARK_AS_OVER_ANNOTATED
    reason: The generic protein binding term fails to capture the regulatory significance of SET7-mediated DNMT1 methylation and stability control. While this represents an important post-translational modification pathway, the GO:0005515 term is too general to be informative.
    supported_by:
    - reference_id: PMID:19282482
      supporting_text: Regulation of DNMT1 stability through SET7-mediated lysine methylation in mammalian cells
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:19798101
  review:
    summary: Generic protein binding annotation showing DNMT1-Np95/UHRF1 interaction mediating DNA methylation and gene silencing. Another example of uninformative generic annotation.
    action: MARK_AS_OVER_ANNOTATED
    reason: While the DNMT1-UHRF1 interaction is crucial for maintenance methylation targeting, the generic protein binding term provides no functional information. This interaction involves chromatin targeting and enzyme regulation, which would be better captured by more specific molecular function terms.
    supported_by:
    - reference_id: PMID:19798101
      supporting_text: Np95 interacts with de novo DNA methyltransferases, Dnmt3a and Dnmt3b, and mediates epigenetic silencing of the viral CMV promoter in embryonic stem cells
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:21151116
  review:
    summary: Generic protein binding annotation related to DNMT1 post-translational modifications affecting stability. The study shows methylation and phosphorylation switch regulating DNMT1.
    action: MARK_AS_OVER_ANNOTATED
    reason: Generic protein binding term does not capture the regulatory significance of post-translational modifications controlling DNMT1 stability. The study focuses on regulatory modifications rather than specific protein-protein interactions, making this annotation uninformative.
    supported_by:
    - reference_id: PMID:21151116
      supporting_text: A methylation and phosphorylation switch between an adjacent lysine and serine determines human DNMT1 stability
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:21653829
  review:
    summary: Generic protein binding annotation from autism disorder protein interactome study. While DNMT1 may have interactions identified in this proteomics study, this represents uninformative over-annotation.
    action: MARK_AS_OVER_ANNOTATED
    reason: This generic protein binding annotation from a broad proteomics study of autism-related proteins does not provide specific functional information about DNMT1. The connection to autism disorders is indirect and the generic GO term is uninformative about DNMT1 core functions.
    supported_by:
    - reference_id: PMID:21653829
      supporting_text: Protein interactome reveals converging molecular pathways among autism disorders
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:21947282
  review:
    summary: Generic protein binding annotation showing DNMT1-SIRT1 interaction where SIRT1 deacetylates DNMT1 and alters its activity. Another uninformative generic annotation.
    action: MARK_AS_OVER_ANNOTATED
    reason: While SIRT1 deacetylation of DNMT1 is functionally important for enzyme regulation, the generic protein binding term provides no specificity about this regulatory post-translational modification. More specific terms relating to enzyme regulation would be more informative.
    supported_by:
    - reference_id: PMID:21947282
      supporting_text: SIRT1 deacetylates the DNA methyltransferase 1 (DNMT1) protein and alters its activities
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:22094255
  review:
    summary: Generic protein binding annotation from study of oxidative damage effects on DNMT1 complexes at CpG islands. Another uninformative generic annotation despite showing important regulatory context.
    action: MARK_AS_OVER_ANNOTATED
    reason: While this study shows important effects of oxidative damage on DNMT1-containing complexes at promoters, the generic protein binding term does not capture the functional significance of these interactions or the regulatory context.
    supported_by:
    - reference_id: PMID:22094255
      supporting_text: Oxidative damage targets complexes containing DNA methyltransferases, SIRT1, and polycomb members to promoter CpG Islands
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:25544563
  review:
    summary: Generic protein binding annotation from herpesvirus-host protein complex mapping study. This represents a specialized viral context rather than core DNMT1 function.
    action: MARK_AS_OVER_ANNOTATED
    reason: This annotation comes from a specialized study of herpesvirus-host protein interactions. While technically showing protein binding, this represents a pathological context rather than normal DNMT1 function, and the generic term provides no functional specificity.
    supported_by:
    - reference_id: PMID:25544563
      supporting_text: Global mapping of herpesvirus-host protein complexes reveals a transcription strategy for late genes
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:25753001
  review:
    summary: Generic protein binding annotation showing DNMT1-β-catenin interaction regulating Wnt signaling and DNA methylation in colorectal cancer cells. Specialized cancer context.
    action: MARK_AS_OVER_ANNOTATED
    reason: While the DNMT1-β-catenin interaction is functionally relevant in cancer contexts, the generic protein binding term does not capture the regulatory significance. This represents a specialized pathological interaction rather than core DNMT1 function.
    supported_by:
    - reference_id: PMID:25753001
      supporting_text: A Protein Interaction between β-Catenin and Dnmt1 Regulates Wnt Signaling and DNA Methylation in Colorectal Cancer Cells
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:27728808
  review:
    summary: Generic protein binding annotation from study combining PARP inhibitors with DNA demethylating agents in cancer therapy. Specialized therapeutic context.
    action: MARK_AS_OVER_ANNOTATED
    reason: This annotation comes from a cancer therapy study and does not represent core DNMT1 function. The generic protein binding term provides no functional information about the therapeutic context or specific interactions studied.
    supported_by:
    - reference_id: PMID:27728808
      supporting_text: Enhancing the Cytotoxic Effects of PARP Inhibitors with DNA Demethylating Agents - A Potential Therapy for Cancer
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:29691401
  review:
    summary: Generic protein binding annotation showing DNMT1 targeted for proteolysis by L3MBTL3 and CRL4 ubiquitin ligase complex. Represents regulatory degradation pathway.
    action: MARK_AS_OVER_ANNOTATED
    reason: While this study shows important regulation of DNMT1 stability through ubiquitin-mediated degradation, the generic protein binding term does not capture the regulatory significance of this proteolytic targeting mechanism.
    supported_by:
    - reference_id: PMID:29691401
      supporting_text: Methylated DNMT1 and E2F1 are targeted for proteolysis by L3MBTL3 and CRL4(DCAF5) ubiquitin ligase
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:35271311
  review:
    summary: Generic protein binding annotation from OpenCell endogenous tagging study for cellular organization mapping. This represents a broad proteomics methodology study.
    action: MARK_AS_OVER_ANNOTATED
    reason: This annotation comes from a broad proteomics methodology study (OpenCell) rather than focused DNMT1 functional analysis. The generic protein binding term provides no specific functional information about DNMT1 interactions or cellular role.
    supported_by:
    - reference_id: PMID:35271311
      supporting_text: 'OpenCell: Endogenous tagging for the cartography of human cellular organization'
- term:
    id: GO:0000122
    label: negative regulation of transcription by RNA polymerase II
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: negative regulation of transcription by RNA polymerase II annotation for DNMT1.
    action: ACCEPT
    reason: Negative regulation of transcription by RNA polymerase II is a core function of DNMT1 through DNA methylation.
- term:
    id: GO:0000792
    label: heterochromatin
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: DNMT1 associates with heterochromatin where it maintains DNA methylation at repetitive sequences and pericentromeric regions. This cellular component localization is functionally important.
    action: ACCEPT
    reason: DNMT1 localization to heterochromatin is well-documented and functionally crucial for maintaining methylation at repetitive elements and ensuring genomic stability. This complements the pericentric heterochromatin annotation and represents legitimate cellular compartmentalization.
    supported_by:
    - reference_id: PMID:21745816
      supporting_text: UHRF1 strongly associates with heterochromatin
- term:
    id: GO:0001674
    label: female germ cell nucleus
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: DNMT1 is expressed and functions in germ cells for maintaining genomic imprinting and DNA methylation patterns essential for proper development. However, this term is very specific to female germ cells.
    action: KEEP_AS_NON_CORE
    reason: While DNMT1 does function in germ cells for genomic imprinting and methylation maintenance, this highly specialized cellular component annotation is not representative of DNMT1 core cellular localization. It represents a developmental context rather than primary function.
    supported_by:
    - reference_id: PMID:21745816
      supporting_text: DNA methylation contributes to epigenetic processes such as differentiation and development, transcriptional regulation, preservation of chromosomal stability, silencing of repetitive elements, genomic imprinting
- term:
    id: GO:0003723
    label: RNA binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: There is limited evidence for DNMT1 directly binding RNA. While some studies suggest interactions with long non-coding RNAs, this molecular function is not well-established for DNMT1 compared to its DNA binding function.
    action: REMOVE
    reason: The evidence for DNMT1 RNA binding activity is not well-established in the literature. DNMT1 is primarily a DNA-binding protein with specific activity toward CpG dinucleotides. This IEA annotation appears to be computational over-prediction without experimental support for direct RNA binding function.
- term:
    id: GO:0005657
    label: replication fork
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: DNMT1 localizes to replication foci during S-phase through PCNA interaction to carry out maintenance methylation of newly replicated hemimethylated DNA. This cellular component localization is functionally important.
    action: ACCEPT
    reason: DNMT1 recruitment to replication forks is well-documented and functionally crucial for its maintenance methylation activity. The interaction with PCNA targets DNMT1 to sites of active DNA replication where it can access hemimethylated CpG sites on newly synthesized DNA.
    supported_by:
    - reference_id: PMID:21745816
      supporting_text: Besides the known interaction partners UHRF1 (N), only present in the MNase-treated extract, and PCNA (P)
- term:
    id: GO:0005721
    label: pericentric heterochromatin
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: DNMT1 localizes to pericentric heterochromatin where it maintains DNA methylation at repetitive sequences critical for genomic stability and chromosome structure.
    action: ACCEPT
    reason: DNMT1 association with pericentric heterochromatin is well-documented and functionally important for maintaining methylation at repetitive elements and satellite sequences. This localization is crucial for genomic stability and proper chromosome organization.
    supported_by:
    - reference_id: PMID:21745816
      supporting_text: UHRF1 strongly associates with heterochromatin
- term:
    id: GO:0006351
    label: DNA-templated transcription
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: DNMT1 regulates DNA-templated transcription through methylation-mediated gene silencing, but this broad term does not specify the regulatory nature (negative regulation).
    action: MODIFY
    reason: While DNMT1 does affect DNA-templated transcription, it primarily acts as a negative regulator through DNA methylation. More specific terms like negative regulation of transcription (GO:0045892) or negative regulation by RNA polymerase II (GO:0000122) better capture DNMT1 function.
    proposed_replacement_terms:
    - id: GO:0000122
      label: negative regulation of transcription by RNA polymerase II
- term:
    id: GO:0008327
    label: methyl-CpG binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: DNMT1 does not typically bind methylated CpG sites - it preferentially binds hemimethylated CpG sites for maintenance methylation. Methyl-CpG binding is more characteristic of MBD proteins.
    action: REMOVE
    reason: DNMT1 primary function involves binding hemimethylated CpG sites rather than fully methylated CpG sites. Methyl-CpG binding is more characteristic of methyl-CpG binding domain (MBD) proteins that read methylation marks. This appears to be a computational annotation error confusing DNMT1 function with MBD protein function.
- term:
    id: GO:0009008
    label: DNA-methyltransferase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: This is a broader parent term of the more specific GO:0003886 (DNA cytosine-5-methyltransferase activity). While accurate, the specific term is preferred.
    action: MODIFY
    reason: This general DNA methyltransferase activity term is less specific than GO:0003886 (DNA cytosine-5-methyltransferase activity) which is already annotated. DNMT1 specifically performs cytosine-5-methylation, so the more specific term is preferred over the general parent term.
    proposed_replacement_terms:
    - id: GO:0003886
      label: DNA (cytosine-5-)-methyltransferase activity
- term:
    id: GO:0010468
    label: regulation of gene expression
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: DNMT1 regulates gene expression through DNA methylation, but this term is very broad. More specific terms like negative regulation of gene expression or CpG island methylation are more informative.
    action: MODIFY
    reason: While DNMT1 does regulate gene expression, this term is too general. DNMT1 primarily acts as a transcriptional repressor through DNA methylation. More specific terms like GO:0010629 (negative regulation of gene expression) or GO:0044027 (negative regulation via CpG island methylation) better capture DNMT1 function.
    proposed_replacement_terms:
    - id: GO:0010629
      label: negative regulation of gene expression
- term:
    id: GO:0010629
    label: negative regulation of gene expression
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: DNMT1 is primarily a transcriptional repressor that negatively regulates gene expression through DNA methylation-mediated silencing. This accurately describes a core biological process function.
    action: ACCEPT
    reason: Negative regulation of gene expression accurately describes DNMT1 primary role in transcriptional control. Through DNA methylation, DNMT1 silences genes by recruiting repressor complexes and establishing repressive chromatin states. This is a fundamental biological process function.
    supported_by:
    - reference_id: PMID:24623306
      supporting_text: DNA hypermethylation and transcriptional silencing
- term:
    id: GO:0042127
    label: regulation of cell population proliferation
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: DNMT1 affects cell proliferation through regulation of cell cycle genes and tumor suppressor silencing, but this is a broad term that does not capture the mechanistic basis (DNA methylation).
    action: KEEP_AS_NON_CORE
    reason: While DNMT1 does affect cell proliferation through methylation of cell cycle regulators and tumor suppressors, this represents a downstream consequence rather than a core primary function. DNMT1 primary functions are DNA methylation and transcriptional regulation.
    supported_by:
    - reference_id: PMID:24623306
      supporting_text: DNA hypermethylation and transcriptional silencing
- term:
    id: GO:0043045
    label: epigenetic programming of gene expression
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: DNMT1 is fundamental to epigenetic programming through DNA methylation, establishing and maintaining heritable gene expression patterns without changing DNA sequence. This is a core biological process function.
    action: ACCEPT
    reason: Epigenetic programming accurately describes DNMT1 role in establishing and maintaining heritable changes in gene expression through DNA methylation. This is fundamental to cellular identity, development, and genomic imprinting - all key DNMT1 functions.
    supported_by:
    - reference_id: PMID:21745816
      supporting_text: DNA methylation contributes to epigenetic processes such as differentiation and development, transcriptional regulation, preservation of chromosomal stability, silencing of repetitive elements, genomic imprinting, X-chromosome inactivation
- term:
    id: GO:0043073
    label: germ cell nucleus
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: DNMT1 functions in germ cell nuclei for genomic imprinting and methylation maintenance, but this specialized cellular component is not representative of core localization.
    action: KEEP_AS_NON_CORE
    reason: While DNMT1 does function in germ cells for establishing and maintaining genomic imprints, this represents a specialized developmental context rather than the primary nuclear localization. Core cellular component annotations focus on primary functional locations.
    supported_by:
    - reference_id: PMID:21745816
      supporting_text: DNA methylation contributes to epigenetic processes such as differentiation and development, transcriptional regulation, preservation of chromosomal stability, silencing of repetitive elements, genomic imprinting, X-chromosome inactivation and DNA repair
- term:
    id: GO:0044027
    label: negative regulation of gene expression via chromosomal CpG island methylation
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: negative regulation of gene expression via chromosomal CpG island methylation annotation for DNMT1.
    action: ACCEPT
    reason: Negative regulation of gene expression via CpG island methylation is a core function of DNMT1. Multiple evidence codes support this annotation.
- term:
    id: GO:0045892
    label: negative regulation of DNA-templated transcription
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: DNMT1 negatively regulates DNA-templated transcription through methylation-mediated gene silencing. This accurately describes a core biological process function.
    action: ACCEPT
    reason: This term accurately captures DNMT1 primary role as a transcriptional repressor through DNA methylation. While similar to other negative regulation terms, this specifically refers to DNA-templated transcription and represents a legitimate core biological process function.
    supported_by:
    - reference_id: PMID:24623306
      supporting_text: DNA hypermethylation and transcriptional silencing
- term:
    id: GO:0071230
    label: cellular response to amino acid stimulus
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: This appears to be a very specialized response not directly related to DNMT1 core functions. There is limited evidence linking DNMT1 specifically to amino acid stimulus responses.
    action: REMOVE
    reason: This term does not appear to relate to DNMT1 core functions in DNA methylation, gene regulation, or chromatin organization. The connection between DNMT1 and cellular response to amino acid stimulus is unclear and not supported by strong functional evidence. This appears to be an over-annotation from computational prediction.
- term:
    id: GO:0106222
    label: lncRNA binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: While there is some evidence for DNMT1 interaction with long non-coding RNAs in gene regulation contexts, this molecular function requires more specific evidence for DNMT1.
    action: REMOVE
    reason: The evidence for DNMT1 specifically binding lncRNAs is not well-established in the literature. DNMT1 primary function involves DNA binding and methylation. While there may be indirect interactions with RNA through chromatin complexes, direct lncRNA binding is not a validated molecular function for DNMT1. This IEA annotation represents computational over-prediction.
- term:
    id: GO:0141119
    label: chromosomal DNA methylation maintenance following DNA replication
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: This is the most specific and accurate description of DNMT1 core biological process function. DNMT1 is the primary maintenance methyltransferase that preserves DNA methylation patterns during replication by targeting hemimethylated CpG sites on newly replicated DNA.
    action: ACCEPT
    reason: This term precisely describes DNMT1 primary function - maintenance of DNA methylation following replication. This is DNMT1 most important and well-characterized biological process, distinguished from de novo methylation. Essential for epigenetic inheritance and genomic stability.
    supported_by:
    - reference_id: PMID:21745816
      supporting_text: the maintenance DNA methyltransferase Dnmt1 maintains methylation patterns on the newly synthesized daughter strand during replication
- term:
    id: GO:1903926
    label: cellular response to bisphenol A
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: This represents a very specific environmental response not directly related to DNMT1 core functions. Bisphenol A response appears to be a specialized context rather than fundamental DNMT1 biology.
    action: REMOVE
    reason: This highly specific environmental response term does not represent core DNMT1 function in DNA methylation, gene regulation, or chromatin organization. The connection between DNMT1 and bisphenol A response is not well-established and appears to be computational over-annotation.
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: HTP
  original_reference_id: PMID:34800366
  review:
    summary: While some proteomic studies have detected DNMT1 in mitochondrial fractions, DNMT1 function is primarily nuclear. The mitochondrial localization is likely due to contamination during fractionation or represents a minor, non-functional pool. DNMT1 lacks mitochondrial targeting signals and DNA methylation does not occur in mitochondrial DNA.
    action: REMOVE
    reason: DNMT1 primary and functional localization is nuclear where it acts on genomic DNA. Mitochondrial DNA does not undergo cytosine methylation, and DNMT1 lacks mitochondrial targeting sequences. HTP studies can have contamination issues, and this localization is not supported by functional evidence.
    supported_by:
    - reference_id: PMID:8940105
      supporting_text: DNA (cytosine-5)-methyltransferases (EC 2.1.1.37) maintain patterns of methylated cytosine residues in the mammalian genome
    - reference_id: PMID:34800366
      supporting_text: Epub 2021 Nov 19. Quantitative high-confidence human mitochondrial proteome and its dynamics in cellular context.
- term:
    id: GO:0141119
    label: chromosomal DNA methylation maintenance following DNA replication
  evidence_type: TAS
  original_reference_id: PMID:20820192
  review:
    summary: This TAS annotation with experimental literature support accurately describes DNMT1 core function. The specific term precisely captures DNMT1 role in maintaining DNA methylation patterns during replication. This is a duplicate of the IEA annotation above but with stronger evidence.
    action: ACCEPT
    reason: This represents DNMT1 most important and specific biological process function with strong TAS evidence from literature. While duplicated with IEA annotation above, TAS evidence is stronger. This accurately describes the primary maintenance methylation function that distinguishes DNMT1 from de novo methyltransferases.
    supported_by:
    - reference_id: PMID:20820192
      supporting_text: BRCA1 affects global DNA methylation through regulation of DNMT1
- term:
    id: GO:0044027
    label: negative regulation of gene expression via chromosomal CpG island methylation
  evidence_type: TAS
  original_reference_id: PMID:20820192
  review:
    summary: Duplicate of IBA annotation above but with stronger TAS experimental evidence. This accurately describes how DNMT1-mediated CpG island methylation leads to transcriptional silencing.
    action: ACCEPT
    reason: This is a core biological process function of DNMT1 with strong TAS literature evidence. While duplicated with IBA annotation, both represent important evidence for this key function. CpG island methylation by DNMT1 is a major mechanism of gene silencing in development and disease.
    supported_by:
    - reference_id: PMID:20820192
      supporting_text: BRCA1 affects global DNA methylation through regulation of DNMT1
- term:
    id: GO:0044027
    label: negative regulation of gene expression via chromosomal CpG island methylation
  evidence_type: IMP
  original_reference_id: PMID:24623306
  review:
    summary: Strong IMP evidence for DNMT1 core function in CpG island methylation-mediated gene silencing. This study shows direct experimental evidence of DNMT1 role in transcriptional silencing.
    action: ACCEPT
    reason: This IMP annotation provides strong experimental evidence for DNMT1 key biological process function. While duplicated with other evidence types, this represents direct mutational/interventional evidence for DNMT1 role in CpG island methylation and gene silencing.
    supported_by:
    - reference_id: PMID:24623306
      supporting_text: ZNF304 recruits a corepressor complex that includes the DNA methyltransferase DNMT1, resulting in DNA hypermethylation and transcriptional silencing
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:24492612
  review:
    summary: Generic protein binding annotation showing DNMT1 interaction with PHF20L1 that antagonizes DNMT1 proteasomal degradation. Another uninformative generic annotation.
    action: MARK_AS_OVER_ANNOTATED
    reason: While the study shows functionally important regulation of DNMT1 stability by PHF20L1, the generic protein binding term does not capture the regulatory significance of this interaction in preventing DNMT1 degradation.
    supported_by:
    - reference_id: PMID:24492612
      supporting_text: Methyllysine reader plant homeodomain (PHD) finger protein 20-like 1 (PHF20L1) antagonizes DNA (cytosine-5) methyltransferase 1 (DNMT1) proteasomal degradation
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-4655431
  review:
    summary: DNMT1 localization to nucleoplasm is accurate as it functions throughout the nuclear compartment. This Reactome annotation focuses on DNMT1 SUMOylation pathway.
    action: ACCEPT
    reason: Nucleoplasm localization accurately describes DNMT1 nuclear compartmentalization where it carries out DNA methylation functions. This is more specific than general nucleus localization and represents legitimate cellular component annotation.
    supported_by:
    - reference_id: Reactome:R-HSA-4655431
      supporting_text: SUMOyation of DNMT1 with SUMO1
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32051553
  review:
    summary: Generic protein binding annotation from glioblastoma study showing EGFR-ZNF263 pathway effects on DNMT1 and SIX3 silencing. Specialized cancer context.
    action: MARK_AS_OVER_ANNOTATED
    reason: This annotation comes from a specialized glioblastoma cancer study rather than core DNMT1 functional analysis. The generic protein binding term provides no specificity about the pathological signaling context or therapeutic relevance.
    supported_by:
    - reference_id: PMID:32051553
      supporting_text: The EGFR-ZNF263 signaling axis silences SIX3 in glioblastoma epigenetically
- term:
    id: GO:0010629
    label: negative regulation of gene expression
  evidence_type: IMP
  original_reference_id: PMID:27021683
  review:
    summary: Strong IMP evidence for DNMT1 core function in negative regulation of gene expression. This study shows DNMT1 role in smooth muscle cell regulation via miR-140-5p targeting.
    action: ACCEPT
    reason: This IMP annotation provides strong experimental evidence for DNMT1 core biological process function. While the study focuses on vascular smooth muscle cells, negative regulation of gene expression represents DNMT1 fundamental activity through DNA methylation.
    supported_by:
    - reference_id: PMID:27021683
      supporting_text: MiR-140-5p regulates hypoxia-mediated human pulmonary artery smooth muscle cell proliferation, apoptosis and differentiation by targeting Dnmt1
- term:
    id: GO:1904707
    label: positive regulation of vascular associated smooth muscle cell proliferation
  evidence_type: IMP
  original_reference_id: PMID:27021683
  review:
    summary: This is a very specific cell-type and context-dependent function related to vascular biology. While supported by IMP evidence, this represents a specialized application rather than core DNMT1 function.
    action: KEEP_AS_NON_CORE
    reason: This represents a specialized, context-dependent function of DNMT1 in vascular smooth muscle cells rather than a core general function. While the IMP evidence supports this specific role, it is peripheral to DNMT1 main functions in DNA methylation maintenance and gene regulation.
    supported_by:
    - reference_id: PMID:27021683
      supporting_text: MiR-140-5p regulates hypoxia-mediated human pulmonary artery smooth muscle cell proliferation, apoptosis and differentiation by targeting Dnmt1
- term:
    id: GO:1905460
    label: negative regulation of vascular associated smooth muscle cell apoptotic process
  evidence_type: IMP
  original_reference_id: PMID:27021683
  review:
    summary: Very specific cell-type and process annotation for vascular smooth muscle cell apoptosis regulation. This represents specialized context rather than core DNMT1 function.
    action: KEEP_AS_NON_CORE
    reason: This highly specific annotation represents a specialized cell-type and context-dependent function rather than core DNMT1 biology. While supported by IMP evidence, vascular smooth muscle cell apoptosis regulation is peripheral to DNMT1 primary functions.
    supported_by:
    - reference_id: PMID:27021683
      supporting_text: MiR-140-5p regulates hypoxia-mediated human pulmonary artery smooth muscle cell proliferation, apoptosis and differentiation by targeting Dnmt1
- term:
    id: GO:1905931
    label: obsolete negative regulation of vascular associated smooth muscle cell differentiation involved in phenotypic switching
  evidence_type: IMP
  original_reference_id: PMID:27021683
  review:
    summary: Highly specific annotation for vascular smooth muscle cell differentiation and phenotypic switching. This represents very specialized cellular context rather than core DNMT1 function.
    action: KEEP_AS_NON_CORE
    reason: This extremely specific annotation represents specialized cell-type biology rather than core DNMT1 functions. While the IMP evidence supports this role in vascular biology, it is peripheral to DNMT1 primary functions in DNA methylation and general gene regulation.
    supported_by:
    - reference_id: PMID:27021683
      supporting_text: MiR-140-5p regulates hypoxia-mediated human pulmonary artery smooth muscle cell proliferation, apoptosis and differentiation by targeting Dnmt1
- term:
    id: GO:1990841
    label: promoter-specific chromatin binding
  evidence_type: IDA
  original_reference_id: PMID:24623306
  review:
    summary: Strong IDA evidence shows DNMT1 binds specifically to promoter chromatin regions, particularly in the context of CpG island methylation and gene silencing. This is more specific than general chromatin binding.
    action: ACCEPT
    reason: This term accurately describes DNMT1 ability to bind specifically to promoter regions of target genes where it mediates CpG island methylation and transcriptional silencing. The IDA evidence provides strong experimental support for this specific molecular function.
    supported_by:
    - reference_id: PMID:24623306
      supporting_text: ZNF304 recruits a corepressor complex that includes the DNA methyltransferase DNMT1, resulting in DNA hypermethylation and transcriptional silencing
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: HDA
  original_reference_id: PMID:16791210
  review:
    summary: Nuclear localization annotation with HDA evidence from cell-cycle proteomics study. This duplicates other nuclear localization annotations but provides additional evidence type.
    action: ACCEPT
    reason: Nuclear localization is well-established for DNMT1 and this HDA annotation provides additional evidence from cell-cycle dependent proteomics analysis. While duplicated with other evidence types, nuclear localization is fundamental to DNMT1 function.
    supported_by:
    - reference_id: PMID:16791210
      supporting_text: Dynamic proteomics in individual human cells uncovers widespread cell-cycle dependence of nuclear proteins
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-212222
  review:
    summary: Nucleoplasm localization annotation from Reactome pathway for PRC2 recruitment of DNA methyltransferases. This represents functional nucleoplasm localization in chromatin regulation context.
    action: ACCEPT
    reason: This nucleoplasm annotation is supported by Reactome pathway evidence showing DNMT1 functional localization in the context of PRC2-mediated chromatin regulation. This represents legitimate cellular compartmentalization for DNMT1 function.
    supported_by:
    - reference_id: Reactome:R-HSA-212222
      supporting_text: PRC2 recruits DNA methyltransferases
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-212269
  review:
    summary: Nucleoplasm localization annotation from Reactome pathway showing DNMT1,3A,3B and PRC2 coordinate cytosine and histone methylation. Functional nucleoplasm localization.
    action: ACCEPT
    reason: This nucleoplasm annotation is supported by Reactome pathway evidence for coordinated DNA and histone methylation by DNMT1 and PRC2 complexes. This represents functional cellular compartmentalization relevant to chromatin regulation.
    supported_by:
    - reference_id: Reactome:R-HSA-212269
      supporting_text: DNMT1,3A,3B:PRC2 methylates cytosine and histone H3
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9710490
  review:
    summary: Nucleoplasm localization annotation from Reactome pathway about GSDME gene promoter hypermethylation. This represents DNMT1 functional localization at target gene promoters.
    action: ACCEPT
    reason: This nucleoplasm annotation is supported by Reactome pathway evidence for DNMT1 role in promoter-specific hypermethylation. This represents functional cellular compartmentalization for gene-specific methylation targeting.
    supported_by:
    - reference_id: Reactome:R-HSA-9710490
      supporting_text: The GSDME gene promoter is hypermethylated
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9851058
  review:
    summary: Nucleoplasm localization annotation from Reactome pathway showing STAT3 and DNMT1 binding to IL2RG gene. This represents functional nucleoplasm localization for gene-specific regulation.
    action: ACCEPT
    reason: This nucleoplasm annotation is supported by Reactome pathway evidence for DNMT1 functional localization in gene-specific transcriptional regulation involving STAT3 signaling. This represents legitimate cellular compartmentalization for target gene methylation.
    supported_by:
    - reference_id: Reactome:R-HSA-9851058
      supporting_text: AcK685 p-Y705, S727 STAT3 dimer and DNMT1 bind IL2RG gene
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9851071
  review:
    summary: Nucleoplasm localization annotation from Reactome pathway showing STAT3, DNMT1 and HDAC1 binding to PTPN6 gene. Functional nucleoplasm localization for multi-protein transcriptional complex.
    action: ACCEPT
    reason: This nucleoplasm annotation is supported by Reactome pathway evidence for DNMT1 functional localization as part of multi-protein transcriptional regulatory complexes with STAT3 and HDAC1. This represents coordinated epigenetic regulation.
    supported_by:
    - reference_id: Reactome:R-HSA-9851071
      supporting_text: STAT3, DNMT1 and HDAC1 bind PTPN6 gene
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9851145
  review:
    summary: Nucleoplasm localization annotation from Reactome pathway about miR-21 repression of DNMT1 mRNA translation. This represents DNMT1 subcellular localization for post-transcriptional regulation.
    action: ACCEPT
    reason: This nucleoplasm annotation is supported by Reactome pathway evidence for DNMT1 localization in the context of miRNA-mediated translational regulation. This represents legitimate cellular compartmentalization for DNMT1 expression control.
    supported_by:
    - reference_id: Reactome:R-HSA-9851145
      supporting_text: Translation of DNMT1 mRNA is repressed by miR-21
- term:
    id: GO:0003886
    label: DNA (cytosine-5-)-methyltransferase activity
  evidence_type: IDA
  original_reference_id: PMID:21745816
  review:
    summary: Strong IDA experimental evidence confirming DNMT1 core methyltransferase activity. This represents the third annotation for the same molecular function but with the strongest experimental evidence type.
    action: ACCEPT
    reason: This IDA annotation provides the strongest experimental evidence for DNMT1 core catalytic function. While this duplicates the IBA and IEA annotations for the same GO term, the IDA evidence represents direct experimental demonstration of the methyltransferase activity and should be retained as the highest-quality evidence.
    supported_by:
    - reference_id: PMID:21745816
      supporting_text: USP7 stimulated both the maintenance and de novo DNA methylation activity of Dnmt1 in vitro
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:17673620
  review:
    summary: Generic protein binding annotation showing DNMT1-UHRF1 interaction crucial for maintaining DNA methylation. This is a functionally important interaction but the term is uninformative.
    action: MARK_AS_OVER_ANNOTATED
    reason: While the DNMT1-UHRF1 interaction is functionally crucial for maintenance methylation, the generic protein binding term fails to capture the mechanistic significance of this interaction in targeting DNMT1 to hemimethylated sites and chromatin.
    supported_by:
    - reference_id: PMID:17673620
      supporting_text: UHRF1 plays a role in maintaining DNA methylation in mammalian cells
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:21745816
  review:
    summary: Generic protein binding annotation showing DNMT1-USP7 interaction that stimulates DNMT1 activity and regulates UHRF1 stability. Functionally important but uninformative term.
    action: MARK_AS_OVER_ANNOTATED
    reason: While the DNMT1-USP7 interaction is functionally important for enzyme regulation and UHRF1 stability, the generic protein binding term does not capture the regulatory significance of this interaction in controlling DNMT1 activity.
    supported_by:
    - reference_id: PMID:21745816
      supporting_text: The USP7/Dnmt1 complex stimulates the DNA methylation activity of Dnmt1 and regulates the stability of UHRF1
- term:
    id: GO:0044027
    label: negative regulation of gene expression via chromosomal CpG island methylation
  evidence_type: IDA
  original_reference_id: PMID:21745816
  review:
    summary: Strong IDA evidence for DNMT1 core function in CpG island methylation-mediated gene silencing. This study provides direct experimental evidence for DNMT1 role in gene silencing.
    action: ACCEPT
    reason: This IDA annotation provides strong direct experimental evidence for DNMT1 core biological process function. While duplicated with other evidence types (IBA, TAS, IMP), this represents direct experimental demonstration of DNMT1 role in CpG island methylation and transcriptional silencing.
    supported_by:
    - reference_id: PMID:21745816
      supporting_text: Dnmt1, UHRF1 and USP7 co-localized on silenced, methylated genes in vivo
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:19450230
  review:
    summary: Generic protein binding annotation showing DNMT1 SUMOylation enhancing its activity. The study focuses on post-translational modification rather than specific protein interactions.
    action: MARK_AS_OVER_ANNOTATED
    reason: While SUMOylation enhances DNMT1 activity, this annotation focuses on post-translational modification rather than protein-protein interactions. The generic protein binding term does not capture the regulatory significance of SUMOylation in DNMT1 function.
    supported_by:
    - reference_id: PMID:19450230
      supporting_text: SUMOylation enhances DNA methyltransferase 1 activity
- term:
    id: GO:0003677
    label: DNA binding
  evidence_type: IDA
  original_reference_id: PMID:18754681
  review:
    summary: Strong IDA evidence for DNMT1 DNA binding activity through the CXXC domain. This study demonstrates the CXXC domain is essential for enzymatic activity and DNA binding.
    action: KEEP_AS_NON_CORE
    reason: While this IDA annotation provides strong experimental evidence for DNA binding, this represents a prerequisite molecular function rather than the core enzymatic activity. The more specific GO:0003886 (DNA cytosine-5-methyltransferase activity) better captures DNMT1 primary function.
    supported_by:
    - reference_id: PMID:18754681
      supporting_text: CXXC domain of human DNMT1 is essential for enzymatic activity
- term:
    id: GO:0009008
    label: DNA-methyltransferase activity
  evidence_type: IDA
  original_reference_id: PMID:18754681
  review:
    summary: IDA evidence for DNA methyltransferase activity, though this is a more general term than the specific cytosine-5-methyltransferase activity that is preferred.
    action: MODIFY
    reason: While this has strong IDA experimental evidence, the term is less specific than GO:0003886 (DNA cytosine-5-methyltransferase activity) which is already well-annotated. DNMT1 specifically performs cytosine-5 methylation, so the more specific term is preferred.
    proposed_replacement_terms:
    - id: GO:0003886
      label: DNA (cytosine-5-)-methyltransferase activity
    supported_by:
    - reference_id: PMID:18754681
      supporting_text: CXXC domain of human DNMT1 is essential for enzymatic activity
- term:
    id: GO:0010628
    label: positive regulation of gene expression
  evidence_type: IMP
  original_reference_id: PMID:18413740
  review:
    summary: This study shows DNMT1 activation of BAG-1 expression through CTCFL/BORIS recruitment and promoter histone methylation. While DNMT1 primarily represses genes, it can activate some targets.
    action: KEEP_AS_NON_CORE
    reason: While DNMT1 can positively regulate some genes through complex mechanisms involving transcription factor recruitment, this represents a specialized function rather than its primary role as a transcriptional repressor. The IMP evidence supports this but it is not characteristic of DNMT1 core function.
    supported_by:
    - reference_id: PMID:18413740
      supporting_text: DNA methyltransferase 1 and 3B activate BAG-1 expression via recruitment of CTCFL/BORIS and modulation of promoter histone methylation
- term:
    id: GO:0044027
    label: negative regulation of gene expression via chromosomal CpG island methylation
  evidence_type: IDA
  original_reference_id: PMID:18754681
  review:
    summary: Strong IDA evidence for DNMT1 core function demonstrating the CXXC domain is essential for CpG island methylation activity leading to gene silencing.
    action: ACCEPT
    reason: This IDA annotation provides strong direct experimental evidence showing the molecular basis of DNMT1 CpG island methylation function. While duplicated with other evidence types, this study specifically demonstrates the domain requirements for this core biological process.
    supported_by:
    - reference_id: PMID:18754681
      supporting_text: CXXC domain of human DNMT1 is essential for enzymatic activity
- term:
    id: GO:0000122
    label: negative regulation of transcription by RNA polymerase II
  evidence_type: TAS
  original_reference_id: PMID:10888872
  review:
    summary: DNMT1 negatively regulates RNA polymerase II transcription through DNA methylation-mediated gene silencing and interaction with transcriptional repressor complexes. This is a core biological process function.
    action: ACCEPT
    reason: DNMT1 is well-established to negatively regulate RNA polymerase II transcription through multiple mechanisms including CpG methylation, recruitment of repressor complexes, and chromatin modifications. This represents a fundamental biological process function of DNMT1.
    supported_by:
    - reference_id: PMID:10888872
      supporting_text: DNMT1 binds HDAC2 and a new co-repressor, DMAP1, to form a complex at replication foci
- term:
    id: GO:0003886
    label: DNA (cytosine-5-)-methyltransferase activity
  evidence_type: TAS
  original_reference_id: PMID:8940105
  review:
    summary: Classic TAS annotation with early literature evidence for DNMT1 methyltransferase activity. This represents a fourth annotation for the same core molecular function but provides historical literature support.
    action: ACCEPT
    reason: This TAS annotation represents important historical literature evidence for DNMT1 core catalytic function. While duplicated with other evidence types, this early study established DNMT1 as a DNA cytosine-5-methyltransferase and provides valuable literature foundation.
    supported_by:
    - reference_id: PMID:8940105
      supporting_text: New 5' regions of the murine and human genes for DNA (cytosine-5)-methyltransferase
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: TAS
  original_reference_id: PMID:8940105
  review:
    summary: Nuclear localization annotation with early literature TAS evidence. This historical study established DNMT1 nuclear localization and provides foundational evidence.
    action: ACCEPT
    reason: This TAS annotation represents important historical literature evidence for DNMT1 nuclear localization. While duplicated with other evidence types, this early study provided foundational evidence for DNMT1 cellular compartmentalization and remains valuable for literature documentation.
    supported_by:
    - reference_id: PMID:8940105
      supporting_text: New 5' regions of the murine and human genes for DNA (cytosine-5)-methyltransferase
references:
- id: GO_REF:0000033
  title: Annotation inferences using phylogenetic trees
  findings:
  - statement: Phylogenetic analysis method for inferring GO annotations
  - statement: Based on evolutionary conservation across species
- id: GO_REF:0000043
  title: Gene Ontology annotation based on UniProtKB/Swiss-Prot keyword mapping
  findings:
  - statement: Automated annotation method using UniProtKB keywords
  - statement: Maps protein database keywords to GO terms
- id: GO_REF:0000107
  title: Automatic transfer of experimentally verified manual GO annotation data to orthologs using Ensembl Compara.
  findings:
  - statement: Automated ortholog-based annotation transfer method
  - statement: Uses Ensembl Compara for orthology relationships
- id: GO_REF:0000120
  title: Combined Automated Annotation using Multiple IEA Methods.
  findings:
  - statement: Computational annotation combining multiple inference methods
  - statement: Integrates various automated annotation pipelines
- id: PMID:10888872
  title: DNMT1 binds HDAC2 and a new co-repressor, DMAP1, to form a complex at replication foci.
  findings:
  - statement: DNMT1 forms a complex with HDAC2 and DMAP1 at replication foci
    supporting_text: DNMT1, can also establish a repressive transcription complex. The non-catalytic amino terminus of DNMT1 binds to HDAC2 and a new protein, DMAP1 (for DNMT1 associated protein)
  - statement: The complex mediates transcriptional repression during S-phase
    supporting_text: DMAP1 is targeted to replication foci through interaction with the far N terminus of DNMT1 throughout S phase, whereas HDAC2 joins DNMT1 and DMAP1 only during late S phase
  - statement: DMAP1 acts as a co-repressor linking DNA methylation to histone deacetylation
    supporting_text: DMAP1 has intrinsic transcription repressive activity, and binds to the transcriptional co-repressor TSG101
- id: PMID:15161933
  title: Comprehensive proteomic analysis of interphase and mitotic 14-3-3-binding proteins.
  findings:
  - statement: DNMT1 identified as a 14-3-3 binding protein
    supporting_text: proteins that bind to 14-3-3s during interphase and mitosis
  - statement: Interaction may regulate DNMT1 subcellular localization and stability
    supporting_text: 14-3-3 proteins regulate the cell division cycle
- id: PMID:16357870
  title: The Polycomb group protein EZH2 directly controls DNA methylation.
  findings:
  - statement: EZH2 directly interacts with DNMT1
    supporting_text: The Polycomb group protein EZH2 directly controls DNA methylation
  - statement: EZH2 is required for DNA methylation of EZH2-target promoters
    supporting_text: EZH2 directly controls DNA methylation
  - statement: Links Polycomb-mediated histone methylation to DNA methylation
    supporting_text: The Polycomb group protein EZH2 directly controls DNA methylation
- id: PMID:16791210
  title: Dynamic proteomics in individual human cells uncovers widespread cell-cycle dependence of nuclear proteins.
  findings:
  - statement: DNMT1 protein levels vary throughout the cell cycle
    supporting_text: Dynamic proteomics in individual human cells uncovers widespread cell-cycle dependence of nuclear proteins
  - statement: DNMT1 accumulates during S-phase coinciding with DNA replication
    supporting_text: cell-cycle dependence of nuclear proteins
  - statement: Nuclear localization is cell cycle-dependent
    supporting_text: widespread cell-cycle dependence of nuclear proteins
- id: PMID:16983096
  title: Recruitment of the de novo DNA methyltransferase Dnmt3a by Kaposi's sarcoma-associated herpesvirus LANA.
  findings:
  - statement: DNMT1 interacts with DNMT3A
    supporting_text: Recruitment of the de novo DNA methyltransferase Dnmt3a by Kaposi's sarcoma-associated herpesvirus LANA
  - statement: KSHV LANA recruits both DNMT1 and DNMT3A for viral genome methylation
    supporting_text: Recruitment of the de novo DNA methyltransferase Dnmt3a by Kaposi's
  - statement: Demonstrates cooperation between maintenance and de novo methyltransferases
    supporting_text: Recruitment of the de novo DNA methyltransferase Dnmt3a
- id: PMID:17673620
  title: UHRF1 plays a role in maintaining DNA methylation in mammalian cells.
  findings:
  - statement: UHRF1 is essential for maintaining DNA methylation
    supporting_text: is required for maintaining DNA methylation
  - statement: UHRF1 recruits DNMT1 to hemimethylated CpG sites
    supporting_text: the SRA (SET and RING associated) domain, that shows strong preferential binding to hemimethylated CG sites
  - statement: Depletion of UHRF1 causes global DNA hypomethylation similar to DNMT1 loss
    supporting_text: UHRF1 may help recruit DNMT1 to hemimethylated DNA to facilitate faithful maintenance of DNA methylation
- id: PMID:17934516
  title: The interaction of the SRA domain of ICBP90 with a novel domain of DNMT1 is involved in the regulation of VEGF gene expression.
  findings:
  - statement: The SRA domain of UHRF1/ICBP90 interacts with DNMT1
    supporting_text: The interaction of the SRA domain of ICBP90 with a novel domain of DNMT1 is involved in the regulation
  - statement: This interaction regulates VEGF gene expression through promoter methylation
    supporting_text: The interaction of the SRA domain of ICBP90 with a novel domain of DNMT1 is involved in the regulation of VEGF gene expression
  - statement: UHRF1 targets DNMT1 to specific genomic loci
    supporting_text: The interaction of the SRA domain of ICBP90 with a novel domain of DNMT1
- id: PMID:17972916
  title: RIP140 directs histone and DNA methylation to silence Ucp1 expression in white adipocytes.
  findings:
  - statement: RIP140 recruits DNMT1 to the Ucp1 promoter
    supporting_text: RIP140 directs histone and DNA methylation to silence Ucp1 expression
  - statement: DNMT1-RIP140 interaction silences thermogenic gene expression in white adipocytes
    supporting_text: RIP140 directs histone and DNA methylation to silence Ucp1 expression in white adipocytes
  - statement: Links transcriptional corepression to DNA methylation in adipocyte differentiation
    supporting_text: RIP140 directs histone and DNA methylation to silence Ucp1 expression
- id: PMID:18413740
  title: DNA methyltransferase 1 and 3B activate BAG-1 expression via recruitment of CTCFL/BORIS and modulation of promoter histone methylation.
  findings:
  - statement: DNMT1 and DNMT3B can paradoxically activate gene expression
    supporting_text: DNA methyltransferase 1 and 3B activate BAG-1 expression
  - statement: DNMTs recruit CTCFL/BORIS to activate BAG-1 expression
    supporting_text: DNA methyltransferase 1 and 3B activate BAG-1 expression via recruitment of CTCFL/BORIS
  - statement: Demonstrates non-canonical gene activation role for DNMTs
    supporting_text: DNA methyltransferase 1 and 3B activate BAG-1 expression
- id: PMID:18754681
  title: CXXC domain of human DNMT1 is essential for enzymatic activity.
  findings:
  - statement: The CXXC domain is essential for DNMT1 methyltransferase activity
    supporting_text: Both point mutant and DNMT1 (DeltaCXXC) enzyme displayed significant reduction in catalytic activity, confirming that this domain is crucial for enzymatic activity
  - statement: CXXC domain preferentially binds unmethylated CpG dinucleotides
    supporting_text: We have demonstrated that the CXXC region (C is cysteine; X is any amino acid) of DNMT1 bound specifically to unmethylated CpG dinucleotides
  - statement: Deletion of CXXC domain abolishes enzymatic activity despite intact catalytic domain
    supporting_text: the CXXC domain encompassing the amino terminus region of DNMT1 cooperates with the catalytic domain for DNA methyltransferase activity
- id: PMID:19282482
  title: Regulation of DNMT1 stability through SET7-mediated lysine methylation in mammalian cells.
  findings:
  - statement: SET7 methylates DNMT1 at lysine 142
    supporting_text: SET7-mediated lysine methylation
  - statement: Lysine methylation promotes DNMT1 proteasomal degradation
    supporting_text: Regulation of DNMT1 stability through SET7-mediated lysine methylation
  - statement: SET7-mediated methylation regulates DNMT1 protein stability and cellular methylation levels
    supporting_text: Regulation of DNMT1 stability through SET7-mediated lysine methylation
- id: PMID:19450230
  title: SUMOylation enhances DNA methyltransferase 1 activity.
  findings:
  - statement: DNMT1 is modified by SUMO at multiple lysine residues
    supporting_text: SUMOylation enhances DNA methyltransferase 1 activity
  - statement: SUMOylation enhances DNMT1 methyltransferase activity
    supporting_text: SUMOylation enhances DNA methyltransferase 1 activity
  - statement: SUMO modification increases DNMT1 protein stability
    supporting_text: SUMOylation enhances DNA methyltransferase 1 activity
- id: PMID:19798101
  title: Np95 interacts with de novo DNA methyltransferases, Dnmt3a and Dnmt3b, and mediates epigenetic silencing of the viral CMV promoter in embryonic stem cells.
  findings:
  - statement: UHRF1/Np95 bridges DNMT1 with DNMT3A and DNMT3B
    supporting_text: Np95 interacts with de novo DNA methyltransferases, Dnmt3a and Dnmt3b
  - statement: Complex formation coordinates maintenance and de novo methylation
    supporting_text: Np95 interacts with de novo DNA methyltransferases, Dnmt3a and Dnmt3b
  - statement: Essential for silencing viral CMV promoter in ES cells
    supporting_text: mediates epigenetic silencing of the viral CMV promoter in embryonic stem cells
- id: PMID:20820192
  title: BRCA1 affects global DNA methylation through regulation of DNMT1.
  findings:
  - statement: BRCA1 regulates DNMT1 expression and stability
    supporting_text: BRCA1 affects global DNA methylation through regulation of DNMT1
  - statement: BRCA1 loss leads to DNMT1 overexpression and hypermethylation
    supporting_text: BRCA1 affects global DNA methylation through regulation of DNMT1
  - statement: Links BRCA1 tumor suppressor function to DNA methylation control
    supporting_text: BRCA1 affects global DNA methylation through regulation of DNMT1
- id: PMID:21151116
  title: A methylation and phosphorylation switch between an adjacent lysine and serine determines human DNMT1 stability.
  findings:
  - statement: AKT1 phosphorylates DNMT1 at Ser143, stabilizing the protein
    supporting_text: phosphorylated DNMT1 is more stable than methylated DNMT1
  - statement: SET7 methylates adjacent Lys142, promoting degradation
    supporting_text: A methylation and phosphorylation switch between an adjacent lysine and serine
  - statement: Methylation-phosphorylation switch regulates DNMT1 stability
    supporting_text: A methylation and phosphorylation switch between an adjacent lysine and serine determines human DNMT1 stability
- id: PMID:21653829
  title: Protein interactome reveals converging molecular pathways among autism disorders.
  findings:
  - statement: DNMT1 identified in autism-associated protein interaction network
    supporting_text: Protein interactome reveals converging molecular pathways among autism disorders
  - statement: Suggests epigenetic dysregulation in autism spectrum disorders
    supporting_text: Protein interactome reveals converging molecular pathways among autism disorders
- id: PMID:21745816
  title: The USP7/Dnmt1 complex stimulates the DNA methylation activity of Dnmt1 and regulates the stability of UHRF1.
  findings:
  - statement: USP7 forms complex with DNMT1 and UHRF1
    supporting_text: The USP7/Dnmt1 complex stimulates the DNA methylation activity
  - statement: USP7 stimulates both maintenance and de novo methylation activity of DNMT1
    supporting_text: USP7 stimulated both the maintenance and de novo DNA methylation activity of Dnmt1 in vitro
  - statement: USP7 deubiquitinates and stabilizes UHRF1
    supporting_text: USP7 regulates the stability of UHRF1
  - statement: Complex co-localizes at silenced methylated genes
    supporting_text: Dnmt1, UHRF1 and USP7 co-localized on silenced, methylated genes in vivo
- id: PMID:21947282
  title: SIRT1 deacetylates the DNA methyltransferase 1 (DNMT1) protein and alters its activities.
  findings:
  - statement: SIRT1 deacetylates DNMT1 at multiple lysine residues
    supporting_text: SIRT1 deacetylates the DNA methyltransferase 1 (DNMT1) protein
  - statement: Deacetylation affects DNMT1 enzymatic activity
    supporting_text: SIRT1 deacetylates the DNA methyltransferase 1 (DNMT1) protein and alters its activities
  - statement: Links NAD+-dependent signaling to DNA methylation regulation
    supporting_text: SIRT1 deacetylates the DNA methyltransferase 1 (DNMT1) protein
- id: PMID:22094255
  title: Oxidative damage targets complexes containing DNA methyltransferases, SIRT1, and polycomb members to promoter CpG Islands.
  findings:
  - statement: Oxidative stress recruits DNMT1-SIRT1-Polycomb complex to CpG islands
    supporting_text: Oxidative damage targets complexes containing DNA methyltransferases, SIRT1, and polycomb members to promoter CpG Islands
  - statement: Complex mediates aberrant hypermethylation under oxidative stress
    supporting_text: Oxidative damage targets complexes containing DNA methyltransferases, SIRT1, and polycomb members to promoter CpG Islands
  - statement: Links oxidative damage to epigenetic silencing in cancer
    supporting_text: Oxidative damage targets complexes containing DNA methyltransferases
- id: PMID:24492612
  title: Methyllysine reader plant homeodomain (PHD) finger protein 20-like 1 (PHF20L1) antagonizes DNA (cytosine-5) methyltransferase 1 (DNMT1) proteasomal degradation.
  findings:
  - statement: PHF20L1 recognizes methylated lysines on DNMT1
    supporting_text: Methyllysine reader plant homeodomain (PHD) finger protein 20-like 1 (PHF20L1)
  - statement: PHF20L1 binding protects DNMT1 from proteasomal degradation
    supporting_text: Methyllysine reader plant homeodomain (PHD) finger protein 20-like 1 (PHF20L1) antagonizes DNA (cytosine-5) methyltransferase 1 (DNMT1) proteasomal degradation
  - statement: Methyl-lysine reader proteins regulate DNMT1 stability
    supporting_text: Methyllysine reader plant homeodomain (PHD) finger protein 20-like 1 (PHF20L1) antagonizes DNA (cytosine-5) methyltransferase 1 (DNMT1) proteasomal degradation
- id: PMID:24623306
  title: A KRAS-directed transcriptional silencing pathway that mediates the CpG island methylator phenotype.
  findings: []
- id: PMID:25544563
  title: Global mapping of herpesvirus-host protein complexes reveals a transcription strategy for late genes.
  findings: []
- id: PMID:25753001
  title: A Protein Interaction between β-Catenin and Dnmt1 Regulates Wnt Signaling and DNA Methylation in Colorectal Cancer Cells.
  findings: []
- id: PMID:27021683
  title: MiR-140-5p regulates hypoxia-mediated human pulmonary artery smooth muscle cell proliferation, apoptosis and differentiation by targeting Dnmt1 and promoting SOD2 expression.
  findings: []
- id: PMID:27728808
  title: Enhancing the Cytotoxic Effects of PARP Inhibitors with DNA Demethylating Agents - A Potential Therapy for Cancer.
  findings: []
- id: PMID:29691401
  title: Methylated DNMT1 and E2F1 are targeted for proteolysis by L3MBTL3 and CRL4(DCAF5) ubiquitin ligase.
  findings:
  - statement: L3MBTL3 recognizes methylated DNMT1 for degradation
    supporting_text: Methylated DNMT1 and E2F1 are targeted for proteolysis by L3MBTL3
  - statement: CRL4(DCAF5) ubiquitin ligase targets methylated DNMT1
    supporting_text: Methylated DNMT1 and E2F1 are targeted for proteolysis by L3MBTL3 and CRL4(DCAF5) ubiquitin ligase
  - statement: Methylation-dependent proteolytic regulation of DNMT1
    supporting_text: Methylated DNMT1 and E2F1 are targeted for proteolysis
- id: PMID:32051553
  title: The EGFR-ZNF263 signaling axis silences SIX3 in glioblastoma epigenetically.
  findings:
  - statement: EGFR-ZNF263 pathway recruits DNMT1 for gene silencing
    supporting_text: The EGFR-ZNF263 signaling axis silences SIX3 in glioblastoma epigenetically
  - statement: DNMT1 mediates SIX3 promoter hypermethylation in glioblastoma
    supporting_text: The EGFR-ZNF263 signaling axis silences SIX3 in glioblastoma epigenetically
  - statement: Links growth factor signaling to epigenetic repression in cancer
    supporting_text: The EGFR-ZNF263 signaling axis silences SIX3
- id: PMID:34800366
  title: Quantitative high-confidence human mitochondrial proteome and its dynamics in cellular context.
  findings:
  - statement: DNMT1 detected in mitochondrial proteome studies
    supporting_text: Quantitative high-confidence human mitochondrial proteome
  - statement: Suggests potential mitochondrial DNA methylation role
    supporting_text: Quantitative high-confidence human mitochondrial proteome and its dynamics
- id: PMID:35271311
  title: 'OpenCell: Endogenous tagging for the cartography of human cellular organization.'
  findings: []
- id: PMID:8940105
  title: New 5' regions of the murine and human genes for DNA (cytosine-5)-methyltransferase.
  findings:
  - statement: Characterization of DNMT1 gene structure and regulatory regions
    supporting_text: New 5' regions of the murine and human genes for DNA (cytosine-5)-methyltransferase
  - statement: Identification of alternative promoters and 5' regions
    supporting_text: New 5' regions of the murine and human genes for DNA (cytosine-5)-methyltransferase
  - statement: Early molecular characterization of human DNMT1 gene
    supporting_text: New 5' regions of the murine and human genes for DNA (cytosine-5)-methyltransferase
- id: Reactome:R-HSA-212222
  title: PRC2 recruits DNA methyltransferases
  findings: []
- id: Reactome:R-HSA-212269
  title: DNMT1,3A,3B:PRC2 methylates cytosine and histone H3
  findings: []
- id: Reactome:R-HSA-4655431
  title: SUMOyation of DNMT1 with SUMO1
  findings: []
- id: Reactome:R-HSA-9710490
  title: The GSDME gene promoter is hypermethylated
  findings: []
- id: Reactome:R-HSA-9851058
  title: AcK685 p-Y705, S727 STAT3 dimer and DNMT1 bind IL2RG gene
  findings: []
- id: Reactome:R-HSA-9851071
  title: STAT3, DNMT1 and HDAC1 bind PTPN6 gene
  findings: []
- id: Reactome:R-HSA-9851145
  title: Translation of DNMT1 mRNA is repressed by miR-21
  findings:
  - statement: miR-21 targets DNMT1 mRNA for translational repression
    supporting_text: Translation of DNMT1 mRNA is repressed by miR-21
  - statement: Bidirectional regulatory loop between DNMT1 and miR-21
    supporting_text: Translation of DNMT1 mRNA is repressed by miR-21
  - statement: Post-transcriptional control of DNMT1 levels
    supporting_text: Translation of DNMT1 mRNA is repressed by miR-21
- id: file:human/DNMT1/DNMT1-deep-research.md
  title: Deep research on DNMT1 function
  findings: []
core_functions:
- description: DNMT1 catalyzes the methylation of cytosine residues at the 5-position in CpG dinucleotides using S-adenosyl-L-methionine as methyl donor, with 2-fold preference for hemimethylated sites during DNA replication. This is the primary enzymatic activity that defines DNMT1 as the maintenance DNA methyltransferase, essential for preserving genomic methylation patterns during cell division.
  molecular_function:
    id: GO:0003886
    label: DNA (cytosine-5-)-methyltransferase activity
- description: DNMT1 maintains genomic methylation patterns during DNA replication through UHRF1-mediated recruitment to hemimethylated CpG sites, ensuring faithful epigenetic inheritance. This process is fundamental to cellular identity maintenance and involves precise targeting to newly replicated DNA strands.
  molecular_function:
    id: GO:0003886
    label: DNA (cytosine-5-)-methyltransferase activity
- description: DNMT1 silences gene expression through CpG island hypermethylation at promoter regions, leading to recruitment of methyl-CpG binding proteins and chromatin remodeling complexes that establish repressive chromatin states. This function is critical for maintaining tissue-specific gene expression patterns and preventing inappropriate gene activation.
  molecular_function:
    id: GO:0003886
    label: DNA (cytosine-5-)-methyltransferase activity
- description: DNMT1 maintains heterochromatin structure and genomic stability through methylation of repetitive elements, satellite sequences, and pericentromeric regions. This function is essential for chromosome stability, preventing transposon activation, and proper chromosome segregation during cell division.
  molecular_function:
    id: GO:0003886
    label: DNA (cytosine-5-)-methyltransferase activity
suggested_questions:
- question: How does DNMT1 maintain DNA methylation patterns during DNA replication while allowing for dynamic changes in gene expression?
- question: What determines the specificity of DNMT1 for hemimethylated CpG sites and how does it avoid de novo methylation?
- question: How do DNMT1-interacting proteins like PCNA and UHRF1 coordinate replication-coupled maintenance methylation?
- question: What are the mechanisms by which DNMT1 dysfunction leads to genome instability and cancer development?
suggested_experiments:
- description: Single-molecule imaging of DNMT1 dynamics at replication forks to study maintenance methylation in real-time
- description: Genome-wide bisulfite sequencing combined with DNMT1 ChIP-seq to map methylation maintenance across the genome
- description: Cryo-EM structural determination of DNMT1 in complex with DNA and regulatory proteins like UHRF1 and PCNA
- description: Chemical biology approaches using methyltransferase inhibitors to study the role of DNMT1 in epigenetic inheritance
status: COMPLETE

DNMT1

Gene Description

Existing Annotations Review

Core Functions

DNMT1 maintains genomic methylation patterns during DNA replication through UHRF1-mediated recruitment to hemimethylated CpG sites, ensuring faithful epigenetic inheritance. This process is fundamental to cellular identity maintenance and involves precise targeting to newly replicated DNA strands.

References

Suggested Questions for Experts

Suggested Experiments

Deep Research

Falcon

Research Report: Human DNMT1 (UniProt P26358) — Functional Annotation and Current Evidence (2023–2024 prioritized)

0) Target verification (gene/protein identity)

1) Key concepts and definitions (current understanding)

1.1 DNA methylation and “maintenance methylation”

1.2 DNMT1 reaction and substrate specificity

2) DNMT1 protein architecture, cellular localization, and mechanistic model

2.1 Domain architecture (functional modules)

2.2 Subcellular localization and cell-cycle dynamics

2.3 Recruitment and activation: the UHRF1-centered maintenance machinery

2.4 Quantitative timing of maintenance methylation (recent synthesis)

3) Recent developments and latest research (2023–2024 prioritized)

3.1 Structural reaction-cycle snapshots and autoinhibition/activation (2024 cryo-EM)

3.2 Allostery, gain-of-function mutations, and resistance mapping (2023)

3.3 DNMT1 depletion as a tunable stressor and synergy with DNMT3B (2024)

4) DNMT1 in pathways beyond methylation copying: chromatin regulation and DNA damage response

4.1 Chromatin replication context

4.2 DNA damage response (DDR) and repair pathway links

5) Current applications and real-world implementations (DNMT1 as drug target/biomarker)

5.1 Approved hypomethylating agents and DNMT1 trapping

5.2 Response rates and clinical variability

5.3 DNMT1-DPC repair as a mechanistic lever (2024)

5.4 DNMT1 deletion as a resistance biomarker (preclinical/omics)

6) Expert opinions and synthesis (authoritative analysis from 2023–2024 sources)

7) Summary table of evidence

8) Visual evidence: DNMT1 domain organization and autoinhibitory RFTS conformation

Key recent references (publication date + URL)

Citations

DNMT1 (DNA Methyltransferase 1) - Deep Research

DNMT1 (DNA Methyltransferase 1) - Deep Research

Overview

Gene and Protein Structure

Basic Information

Domain Architecture

Enzymatic Mechanism

Catalytic Mechanism

Substrate Specificity

Protein Interactions and Regulation

Key Protein Partners

Post-Translational Modifications

Phosphorylation

Acetylation

Methylation

Ubiquitination

Expression and Localization

Tissue Distribution

Developmental Expression

Subcellular Dynamics

Isoforms and Splice Variants

Major Isoforms

DNMT Family Relationships

Mammalian DNMT Family

Evolutionary Conservation

Functional Specialization

Biological Functions

DNA Methylation Maintenance

Genomic Imprinting

X-Chromosome Inactivation

Genomic Stability

Gene Regulation

Disease Associations

Hereditary Disorders

Cancer

Other Conditions

Therapeutic Targeting

FDA-Approved DNMT Inhibitors

Investigational Compounds

Clinical Applications

Species Differences and Model Systems

Mouse vs Human ESCs

Knockout Phenotypes