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FLASH GENE

Symbol

DNMT1

contributors: shn/mct - updated : 22-12-2016

HGNC name	DNA (cytosine-5-)-methyltransferase 1
HGNC id	2976

FLASH GENE DNA RNA EXPRESSION PROTEIN DISORDER ANIMAL & CELL MODELS

Corresponding disease	ADCADN cerebellar ataxia, deafness, and narcolepsy, autosomal dominant HSANDHL hereditary sensory and autonomic neuropathy with dementia and hearing loss
Location	19p13.2      Physical location : 10.244.022 - 10.305.755
Synonym name	DNA methyltransferase 1
	DNA (cytosine-5)-methyltransferase 1
	DNA MTase HsaI
	DNA methyltransferase HsaI
	m.HsaI
	CXXC finger protein 9
	CXXC-type zinc finger protein 9
Synonym symbol(s)	MCMT, DNMT, AIM, DNM1, CXXC9, FLJ16293, MGC104992, ADCADN
EC.number	2.1.1.37

DNA

TYPE	functioning gene
STRUCTURE	61.73 kb     41 Exon(s)

10 Kb 5' upstream gene genomic sequence study

regulatory sequence	Promoter
	Binding site   transcription factor
text structure	promoter is a TATA-less promoter and therefore its transcriptional activity is highly dependent on the binding of transcription factors to the basal promoter region
	E2F-binding site located within the transcription initiation region is critical for the regulation of DNMT1 transcription in proliferating cells via the E2F1/pRB pathway

MAPPING

cloned

Y

linked

N

status

confirmed

Map	pter - D19S586 - D19S583 - DNMT1 - D19S584 - D19S906 - cen

RNA

TRANSCRIPTS	type	messenger

identification nb exons type bp product Protein kDa AA specific expression Year Pubmed NM_001130823 41 - 5425 NP_001124295 183 1632 - 2010 20081831 also called DNMT1a NM_001379 40 splicing 5377 NP_001370 - 1616 less expressed 2010 20081831 also called DNMT1f insertion of 48bp from intron 4 becoming exon 5a

EXPRESSION

Type	ubiquitous

expressed in

(based on citations)

organ(s)

System Organ level 1 Organ level 2 Organ level 3 Organ level 4 Level Pubmed Species Stage Rna symbol Digestive liver         Hearing/Equilibrium ear       highly Lymphoid/Immune lymph node       predominantly   thymus       moderately Nervous brain         Reproductive female system uterus cervix   highly   female system breast mammary gland   moderately Respiratory lung         Skin/Tegument skin       highly Urinary kidney

tissue

System Tissue Tissue level 1 Tissue level 2 Level Pubmed Species Stage Rna symbol Epithelial barrier lining epidermis stratum basale highly Muscular striatum skeletal

cell lineage	expressed in epidermal progenitor-containing cell populations and is lost during differentiation
cell lines	abundantly, in cell lines
fluid/secretion	moderately in blood, highly in lymph

at STAGE

cell cycle

cell cycle, S

Text	reduced to non detectable levels at the G0 phase of the cell cycle and dramatically induced upon entrance into the S-phase of the cell cycle

IMPRINTING
text	paternally expressed and methylated specifically on the maternal allele in the human placenta

PROTEIN

PHYSICAL PROPERTIES

STRUCTURE

motifs/domains	N terminal nuclear localization signal (NLS), replication foci-targeting sequences and interacting with several proteins such as DMAP1, HDAC2 (histone deacetylase), PCNA and RB
	the zinc binding region with the cysteine-rich (CXXC) motif, that bound specifically to unmethylated CpG dinucleotides, encompassing the N-terminus region of DNMT1 and cooperating with the catalytic domain for DNA methyltransferase activity
	two BAH domains
	a bromodomain
	a C terminal region with five conserved motifs involved in catalytic activities, alternatively spliced, DNMT catalytic domain

HOMOLOGY

interspecies	ortholog to DNMT1, Pan troglodytes
	ortholog to dnmt1, Danio rerio
	ortholog to Dnmt1, Rattus norvegicus
	ortholog to Dnmt1, Mus musculus

Homologene

FAMILY

C5-methyltransferase family

CATEGORY

enzyme

SUBCELLULAR LOCALIZATION	intracellular
	intracellular,cytoplasm,organelle,mitochondria,matrix
	intracellular,nucleus,nucleoplasm
	intracellular,nucleus,chromatin/chromosome,heterochromosome
text	replication fork
	binds to mtDNA, proving the presence of mtDNMT1 in the mitochondrial matrix

basic FUNCTION	involved in the maintenance of DNA-methylation activities
	required to maintain global methylation and aberrant CpG island methylation in cancers
	playing a role in the mismatch repair gene
	involved in the methylation maintenance transcription repression
	acting as a putative mediator of the methylation process and cooperating with RB to repress transcription from promoters containing E2F binding sites
	may be the enzyme primarily responsible for maintenance of the global methylation status of genomic DNA
	contributing to the preservation of the correct organization of large heterochromatic regions
	required for maintenance of bulk DNA methylation, and essential for maintenance of DNA methylation, proliferation, and survival of cancer cells
	being responsible for maintaining methylation patterns established in development
	regulates BAG-1 expression via insulator protein DNA-binding and chromatin dynamics by regulating histone dimethylation
	responsible for the aberrant hypermethylation of CpG islands and the silencing of tumor suppressor genes
	crucial transcription regulator for DNMT1
	maintains DNA methylation patterns after cellular replication, and essential for epidermal progenitor cell function
	acting as a maintenance methyltransferase, playing an essential role in the faithful propagation of the genomic methylation profile from mother to daughter cells following cell division
	may participate in sensing DNA damage, in one of the cell-cycle checkpoints, or in both
	acting as a regulator of genome integrity and as an early responder to DNA DSBs
	recruited early and transiently to DSBs by multiple DNA damage-related interactions and that it plays a role in modulating the cellular response to DNA damage
	both DNMT1 and UHRF1 coprecipitate with ubiquitin specific peptidase 7 (USP7), a de-ubiquitinating enzyme
	appears to be capable of both initiating and maintaining cytosine methylation in the nucleus, and the lack of de novo methyltransferases in mitochondria implicates mtDNMT1 in both processes in this organelle
	most prevalent DNA methyltransferase found in cells and which is responsible for maintaining the DNA methylation patterns once formed
	link between DNMT1 insufficiency and genomic instability
	DNA methyltransferase maintaining methylation patterns in development, and mediating transcriptional repression by direct binding to HDAC2
	required for the differentiation of CD4+ into T regulatory cells
	tethered to the DNA replication fork and is the major player in maintaining DNA methylation patterns during replication
	DNMT3A, DNMT3B, DNMT1 roles in Ca(2+) ion-dependent biological processes, including the genome-wide/local DNA demethylation during early embryogenesis, cell differentiation, neuronal activity-regulated gene expression, and carcinogenesis
	is required to maintain HbF silencing in primary human adult erythroid cells
	role for DNMT1 in modulating the timing of differentiation and describe a novel ATP-citrate lyase (ACL)-miR148a-dependent mechanism for regulating DNMT1 during adipogenesis
	key enzyme involved in the somatic inheritance of DNA methylation and thus plays a critical role in epigenomic stability
	is critical for the prevention and maintenance of T-cell lymphomas and contributes to aberrant methylation by both de novo and maintenance methylation
	MYB and BCL11A cooperate with DNMT1 to achieve developmental repression of embryonic and fetal beta-like globin genes in the adult erythroid environment
	primary enzyme that maintains DNA methylation during replication
	regulation of DNMT1 is critical for epigenetic control of many genes and for genome stability
	is crucial during perinatal intestinal development
	essential role in maintaining genomic stability during intestinal development and the establishment of intestinal crypts
	responsible for propagating the DNA methylation patterns during DNA replication

CELLULAR PROCESS	nucleotide, chromatin organization, methylation
	nucleotide, transcription, regulation

PHYSIOLOGICAL PROCESS

development , immunity/defense

PATHWAY

metabolism

signaling

CDKN1A-EP300-DNMT1 pathway may play a pivotal role to ensure regulated DNMT1 expression and DNA methylation in mammalian cell division

a component	complexing with RB1, E2E1, HDAC1 and BB1
	also complexing with HDAC2, DMAP1
	component of complexes containing SUV39H1
	KAT5, UHRF1, HDAC1 and DNMT1 are present in the same macro-molecular complex and are partners for the epigenetic code inheritance

INTERACTION

DNA	interaction of mtDNMT1 with mtDNA is potentially proportional to CpG density, supporting a functional role for mtDNMT1 in establishment and maintenance of mtDNA methylation

RNA

small molecule

protein	proliferating cell nuclear antigen, PCNA
	MBD2 and MBD3
	HDAC1 and E2F1
	cooperating with DNMT3A for de novo methylation of DNA
	STAT3 and HDAC1 for epigenetic silencing of PTPN6 in various tumors
	histone deacetylase 2, HDAC2 and DNA methyltransferase 1 associated protein 1, DMAP1
	DNMT3a and DNMT3b
	retinoblastoma protein, RB
	SUV39H1 histone methyltransferase
	methyl CpG binding protein 2, MECP2
	regulator of G-protein signaling 6, RGS6
	HESX1
	CXXC finger 1 (PHD domain), CXXC1
	SRA domain of SRA domain of ICBP90
	AOF2 (demethylates and stabilizes DNMT1, thus providing a previously unknown mechanistic link between the histone and DNA methylation systems)
	UHRF1 through SET and RING finger-associated (SRA) domain
	NAA10 is an oncoprotein, but it contributes to oncogenesis through modulation of DNMT1 function
	SETD7 regulates DNA methyltransferase-1 (DNMT1) activity in mammalian cells by promoting degradation of DNMT1 and thus allows epigenetic changes via DNA demethylation
	binding of CDK5 to the N-terminal domain of DNMT1
	USP7 is an interaction partner of DNMT1 and UHRF1
	SIRT1 regulates the activities of DNMT1, a key enzyme responsible for DNA methylation
	operates either as a functional intermediary or in cooperation with E2F1 inhibiting AR gene expression in a methylation independent manner
	DNMT1 function in the regulatory response is controlled by NBN
	DNMT1 directly interacts with the SET and RING finger-associated (SRA) domain of UHRF1 to facilitate accession of the catalytic center to hemi-methylated DNA
	interaction with UHRF1 increased the specificity of DNMT1 for methylation of hemimethylated CpG sites)
	interaction between DNMT1 and MBD4 is involved in controlling gene expression and responding to oxidative stress
	NFKB1 inactivation diminished, whereas NFKB1 overexpression enhanced DNMT1 promoter activity and endogenous DNMT1 expression
	RB1 maintains quiescence and prevents premature senescence through upregulation of DNMT1 in mesenchymal stromal cells
	both DNMT1 and methyl-CpG-binding domain Protein 4 (MBD4) bind to the TNFRSF18
	ZNF479 induced the expression of DNMT1, UHRF1, and mixed-lineage leukemia (MLL) complex proteins (ASH2L and Menin), and increased tri-methylated histone H3 (H3K4me3) levels, but suppressed H3K4 (H3K4me2) di-methylation

cell & other

REGULATION

activated by

DMAP1 (activates DNMT1 preferentially at sites of homologous recombination repair)

Phosphorylated by

CDKs at Ser154 whichis important for enzymatic activity and protein stability of DNMT1

Other	SUMOylated which significantly enhances its methylase activity
	regulation through modifications mediated by AKT1 and SETD7, that affects cellular DNMT1 levels

ASSOCIATED DISORDERS

corresponding disease(s)

HSANDHL , ADCADN

Other morbid association(s)

Type Gene Modification Chromosome rearrangement Protein expression Protein Function constitutional     --over   in telencephalic GABAergic interneurons of schizophrenia brain tumoral       gain of function in leukemia constitutional     --low   by specific hypermethylation in placenta, and promoter methylation attenuates transcriptional activity in trophoblast cells tumoral     --low   responsible for induction of DDX53 drug-resistant cancer cells constitutional         affect the DNA damage response (DDR) in the cell constitutional     --over   by hypomethylation involved in other autoimmune diseases such as lupus

Susceptibility

to autoimmune disease

Variant & Polymorphism SNP	increasing the risk of autoimmune disease

Candidate gene
Marker
Therapy target
	System Type Disorder Pubmed cancer     development of novel combination therapies that will exploit DNMT1 role not only as a maintenance methyltransferase, but also as a modulator of the DNA damage response, to more efficiently target tumor cells for destruction

ANIMAL & CELL MODELS

	Dnmt1 mutant mice with 90% of hypomethylated cortical and hippocampal cells in the dorsal forebrain from E13.5 on are viable but display severe neuronal cell death between E14.5
	conditional mutant mice lacking Dnmt1 and Dnmt3 in forebrain excitatory neurons have abnormal long-term plasticity in the hippocampal CA1 region with deficits in learning and memory