Q8NFU7 (TET1_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
Methylcytosine dioxygenase TET1
EC=1.14.11.n2

Alternative name(s):
CXXC-type zinc finger protein 6
Leukemia-associated protein with a CXXC domain
Ten-eleven translocation 1 gene protein

Gene names

Name:	TET1
Synonyms:	CXXC6, KIAA1676, LCX

Organism

Homo sapiens (Human) [Reference proteome]

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

cellular organisms › Eukaryota › Opisthokonta › Metazoa › Eumetazoa › Bilateria › Deuterostomia › Chordata › Craniata › Vertebrata › Gnathostomata › Teleostomi › Euteleostomi › Sarcopterygii › Tetrapoda › Amniota › Mammalia › Theria › Eutheria › Euarchontoglires › Primates › Haplorrhini › Simiiformes › Catarrhini › Hominoidea › Hominidae › Homininae › Homo

Protein attributes

Sequence length	2136 AA.
Sequence status	Complete.
Protein existence	Evidence at protein level

General annotation (Comments)

Function	Dioxygenase that catalyzes the conversion of the modified genomic base 5-methylcytosine (5mC) into 5-hydroxymethylcytosine (5hmC) and plays a key role in active DNA demethylation. Also mediates subsequent conversion of 5hmC into 5-formylcytosine (5fC), and conversion of 5fC to 5-carboxylcytosine (5caC). Conversion of 5mC into 5hmC, 5fC and 5caC probably constitutes the first step in cytosine demethylation. Methylation at the C5 position of cytosine bases is an epigenetic modification of the mammalian genome which plays an important role in transcriptional regulation. In addition to its role in DNA demethylation, plays a more general role in chromatin regulation. Preferentially binds to CpG-rich sequences at promoters of both transcriptionally active and Polycomb-repressed genes. Involved in the recruitment of the O-GlcNAc transferase OGT to CpG-rich transcription start sites of active genes, thereby promoting histone H2B GlcNAcylation by OGT. Also involved in transcription repression of a subset of genes through recruitment of transcriptional repressors to promoters. Involved in the balance between pluripotency and lineage commitment of cells it plays a role in embryonic stem cells maintenance and inner cell mass cell specification. Ref.1 Ref.7 Ref.8 Ref.9 Ref.11
Catalytic activity	DNA 5-methylcytosine + 2-oxoglutarate + O2 = DNA 5-hydroxymethylcytosine + succinate + CO2. Ref.8 Ref.9 DNA 5-hydroxymethylcytosine + 2-oxoglutarate + O2 = DNA 5-formylcytosine + succinate + CO2. Ref.8 Ref.9 DNA 5-formylcytosine + 2-oxoglutarate + O2 = DNA 5-carboxylcytosine + succinate + CO2. Ref.8 Ref.9
Cofactor	Binds 1 Fe2+ ion per subunit. Ref.8
Subunit structure	Interacts with HCFC1 and OGT By similarity. Interacts with SIN3A; recruits the transcriptional corepressor SIN3A to gene promoters. Ref.10
Subcellular location	Nucleus Probable.
Tissue specificity	Expressed in fetal heart, lung and brain, and in adult skeletal muscle, thymus and ovary. Not detected in adult heart, lung or brain. Ref.1 Ref.6
Post-translational modification	Glycosylated. Interaction with OGT leads to GlcNAcylation By similarity.
Involvement in disease	A chromosomal aberration involving TET1 may be a cause of acute leukemias. Translocation t(10;11)(q22;q23) with MLL. This is a rare chromosomal translocation 5' MLL-TET1 3'.
Sequence similarities	Belongs to the TET family. Contains 1 CXXC-type zinc finger.
Caution	Subsequent steps in cytosine demethylation are subject to discussion. According to a first model cytosine demethylation occurs through deamination of 5hmC into 5-hydroxymethyluracil (5hmU) and subsequent replacement by unmethylated cytosine by the base excision repair system (Ref.9). According to another model, cytosine demethylation is rather mediated via conversion of 5hmC into 5fC and 5caC, followed by excision by TDG and replacement by unmethylated cytosine.
Sequence caution	The sequence CAD28467.3 differs from that shown. Reason: Contaminating sequence. Potential poly-A sequence.

Ontologies

Keywords
Biological process	Transcription Transcription regulation
Cellular component	Nucleus
Coding sequence diversity	Chromosomal rearrangement Polymorphism
Domain	Zinc-finger
Ligand	DNA-binding Iron Metal-binding Zinc
Molecular function	Activator Chromatin regulator Dioxygenase Oxidoreductase Repressor
PTM	Glycoprotein
Technical term	Complete proteome Reference proteome
Gene Ontology (GO)
Biological_process	DNA demethylation Inferred from mutant phenotype Ref.9. Source: UniProtKB chromatin modification Inferred from electronic annotation. Source: UniProtKB-KW inner cell mass cell differentiation Inferred from sequence or structural similarity. Source: UniProtKB negative regulation of methylation-dependent chromatin silencing Inferred from mutant phenotype Ref.9. Source: UniProtKB positive regulation of transcription from RNA polymerase II promoter Inferred from sequence or structural similarity. Source: UniProtKB protein O-linked glycosylation Inferred from sequence or structural similarity. Source: UniProtKB regulation of DNA methylation Inferred from electronic annotation. Source: Compara stem cell maintenance Inferred from sequence or structural similarity. Source: UniProtKB transcription, DNA-dependent Inferred from electronic annotation. Source: UniProtKB-KW
Cellular_component	nucleus Inferred by curator Ref.8. Source: UniProtKB
Molecular_function	iron ion binding Inferred from direct assay Ref.8. Source: UniProtKB methylcytosine dioxygenase activity Inferred from direct assay Ref.8. Source: UniProtKB oxidoreductase activity, acting on single donors with incorporation of molecular oxygen, incorporation of two atoms of oxygen Inferred from electronic annotation. Source: UniProtKB-KW structure-specific DNA binding Inferred from direct assay Ref.8. Source: UniProtKB zinc ion binding Inferred from electronic annotation. Source: InterPro
Complete GO annotation...

Sequence annotation (Features)

	Feature key	Position(s)	Length	Description	Graphical view	Feature identifier
Molecule processing
	Chain	1 – 2136	2136	Methylcytosine dioxygenase TET1		PRO_0000251949
Regions
	Zinc finger	584 – 625	42	CXXC-type
	Region	528 – 674	147	Sufficient for binding to genomic CpG islands
Sites
	Metal binding	1672	1	Iron; catalytic
	Metal binding	1674	1	Iron; catalytic
	Metal binding	2028	1	Iron; catalytic By similarity
	Binding site	2043	1	2-oxoglutarate By similarity
	Site	1608 – 1609	2	Breakpoint for translocation to form MLL-TET1 oncogene
Natural variations
	Natural variant	162	1	D → G. Corresponds to variant rs10823229 [ dbSNP | Ensembl ].		VAR_027734
	Natural variant	193	1	S → T. Corresponds to variant rs12773594 [ dbSNP | Ensembl ].		VAR_027735
	Natural variant	256	1	A → V. Corresponds to variant rs12221107 [ dbSNP | Ensembl ].		VAR_027736
	Natural variant	1018	1	N → S. Corresponds to variant rs16925541 [ dbSNP | Ensembl ].		VAR_027737
	Natural variant	1123	1	I → M. Ref.1 Corresponds to variant rs3998860 [ dbSNP | Ensembl ].		VAR_027738
Experimental info
	Mutagenesis	1672	1	H → Y: Loss of catalytic activity and loss of the ability to induce DNA demethylation. Ref.8 Ref.9
	Mutagenesis	1674	1	D → A: Loss of catalytic activity and loss of the ability to induce DNA demethylation. Ref.8 Ref.9
	Sequence conflict	2001	1	F → L in CAD28467. Ref.4

Sequences

	Sequence		Length	Mass (Da)
	Q8NFU7 [UniParc]. Last modified October 3, 2006. Version 2. Checksum: 66E24EF0594A964C	FASTA	2,136	235,309
	10 20 30 40 50 60 MSRSRHARPS RLVRKEDVNK KKKNSQLRKT TKGANKNVAS VKTLSPGKLK QLIQERDVKK 70 80 90 100 110 120 KTEPKPPVPV RSLLTRAGAA RMNLDRTEVL FQNPESLTCN GFTMALRSTS LSRRLSQPPL 130 140 150 160 170 180 VVAKSKKVPL SKGLEKQHDC DYKILPALGV KHSENDSVPM QDTQVLPDIE TLIGVQNPSL 190 200 210 220 230 240 LKGKSQETTQ FWSQRVEDSK INIPTHSGPA AEILPGPLEG TRCGEGLFSE ETLNDTSGSP 250 260 270 280 290 300 KMFAQDTVCA PFPQRATPKV TSQGNPSIQL EELGSRVESL KLSDSYLDPI KSEHDCYPTS 310 320 330 340 350 360 SLNKVIPDLN LRNCLALGGS TSPTSVIKFL LAGSKQATLG AKPDHQEAFE ATANQQEVSD 370 380 390 400 410 420 TTSFLGQAFG AIPHQWELPG ADPVHGEALG ETPDLPEIPG AIPVQGEVFG TILDQQETLG 430 440 450 460 470 480 MSGSVVPDLP VFLPVPPNPI ATFNAPSKWP EPQSTVSYGL AVQGAIQILP LGSGHTPQSS 490 500 510 520 530 540 SNSEKNSLPP VMAISNVENE KQVHISFLPA NTQGFPLAPE RGLFHASLGI AQLSQAGPSK 550 560 570 580 590 600 SDRGSSQVSV TSTVHVVNTT VVTMPVPMVS TSSSSYTTLL PTLEKKKRKR CGVCEPCQQK 610 620 630 640 650 660 TNCGECTYCK NRKNSHQICK KRKCEELKKK PSVVVPLEVI KENKRPQREK KPKVLKADFD 670 680 690 700 710 720 NKPVNGPKSE SMDYSRCGHG EEQKLELNPH TVENVTKNED SMTGIEVEKW TQNKKSQLTD 730 740 750 760 770 780 HVKGDFSANV PEAEKSKNSE VDKKRTKSPK LFVQTVRNGI KHVHCLPAET NVSFKKFNIE 790 800 810 820 830 840 EFGKTLENNS YKFLKDTANH KNAMSSVATD MSCDHLKGRS NVLVFQQPGF NCSSIPHSSH 850 860 870 880 890 900 SIINHHASIH NEGDQPKTPE NIPSKEPKDG SPVQPSLLSL MKDRRLTLEQ VVAIEALTQL 910 920 930 940 950 960 SEAPSENSSP SKSEKDEESE QRTASLLNSC KAILYTVRKD LQDPNLQGEP PKLNHCPSLE 970 980 990 1000 1010 1020 KQSSCNTVVF NGQTTTLSNS HINSATNQAS TKSHEYSKVT NSLSLFIPKS NSSKIDTNKS 1030 1040 1050 1060 1070 1080 IAQGIITLDN CSNDLHQLPP RNNEVEYCNQ LLDSSKKLDS DDLSCQDATH TQIEEDVATQ 1090 1100 1110 1120 1130 1140 LTQLASIIKI NYIKPEDKKV ESTPTSLVTC NVQQKYNQEK GTIQQKPPSS VHNNHGSSLT 1150 1160 1170 1180 1190 1200 KQKNPTQKKT KSTPSRDRRK KKPTVVSYQE NDRQKWEKLS YMYGTICDIW IASKFQNFGQ 1210 1220 1230 1240 1250 1260 FCPHDFPTVF GKISSSTKIW KPLAQTRSIM QPKTVFPPLT QIKLQRYPES AEEKVKVEPL 1270 1280 1290 1300 1310 1320 DSLSLFHLKT ESNGKAFTDK AYNSQVQLTV NANQKAHPLT QPSSPPNQCA NVMAGDDQIR 1330 1340 1350 1360 1370 1380 FQQVVKEQLM HQRLPTLPGI SHETPLPESA LTLRNVNVVC SGGITVVSTK SEEEVCSSSF 1390 1400 1410 1420 1430 1440 GTSEFSTVDS AQKNFNDYAM NFFTNPTKNL VSITKDSELP TCSCLDRVIQ KDKGPYYTHL 1450 1460 1470 1480 1490 1500 GAGPSVAAVR EIMENRYGQK GNAIRIEIVV YTGKEGKSSH GCPIAKWVLR RSSDEEKVLC 1510 1520 1530 1540 1550 1560 LVRQRTGHHC PTAVMVVLIM VWDGIPLPMA DRLYTELTEN LKSYNGHPTD RRCTLNENRT 1570 1580 1590 1600 1610 1620 CTCQGIDPET CGASFSFGCS WSMYFNGCKF GRSPSPRRFR IDPSSPLHEK NLEDNLQSLA 1630 1640 1650 1660 1670 1680 TRLAPIYKQY APVAYQNQVE YENVARECRL GSKEGRPFSG VTACLDFCAH PHRDIHNMNN 1690 1700 1710 1720 1730 1740 GSTVVCTLTR EDNRSLGVIP QDEQLHVLPL YKLSDTDEFG SKEGMEAKIK SGAIEVLAPR 1750 1760 1770 1780 1790 1800 RKKRTCFTQP VPRSGKKRAA MMTEVLAHKI RAVEKKPIPR IKRKNNSTTT NNSKPSSLPT 1810 1820 1830 1840 1850 1860 LGSNTETVQP EVKSETEPHF ILKSSDNTKT YSLMPSAPHP VKEASPGFSW SPKTASATPA 1870 1880 1890 1900 1910 1920 PLKNDATASC GFSERSSTPH CTMPSGRLSG ANAAAADGPG ISQLGEVAPL PTLSAPVMEP 1930 1940 1950 1960 1970 1980 LINSEPSTGV TEPLTPHQPN HQPSFLTSPQ DLASSPMEED EQHSEADEPP SDEPLSDDPL 1990 2000 2010 2020 2030 2040 SPAEEKLPHI DEYWSDSEHI FLDANIGGVA IAPAHGSVLI ECARRELHAT TPVEHPNRNH 2050 2060 2070 2080 2090 2100 PTRLSLVFYQ HKNLNKPQHG FELNKIKFEA KEAKNKKMKA SEQKDQAANE GPEQSSEVNE 2110 2120 2130 LNQIPSHKAL TLTHDNVVTV SPYALTHVAG PYNHWV

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"LCX, leukemia-associated protein with a CXXC domain, is fused to MLL in acute myeloid leukemia with trilineage dysplasia having t(10;11)(q22;q23)." Ono R., Taki T., Taketani T., Taniwaki M., Kobayashi H., Hayashi Y. Cancer Res. 62:4075-4080(2002) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA], VARIANT MET-1123, FUNCTION, TISSUE SPECIFICITY, CHROMOSOMAL TRANSLOCATION WITH MLL. Tissue: Leukemia.
[2]	"The DNA sequence and comparative analysis of human chromosome 10." Deloukas P., Earthrowl M.E., Grafham D.V., Rubenfield M., French L., Steward C.A., Sims S.K., Jones M.C., Searle S., Scott C., Howe K., Hunt S.E., Andrews T.D., Gilbert J.G.R., Swarbreck D., Ashurst J.L., Taylor A., Battles J. , Bird C.P., Ainscough R., Almeida J.P., Ashwell R.I.S., Ambrose K.D., Babbage A.K., Bagguley C.L., Bailey J., Banerjee R., Bates K., Beasley H., Bray-Allen S., Brown A.J., Brown J.Y., Burford D.C., Burrill W., Burton J., Cahill P., Camire D., Carter N.P., Chapman J.C., Clark S.Y., Clarke G., Clee C.M., Clegg S., Corby N., Coulson A., Dhami P., Dutta I., Dunn M., Faulkner L., Frankish A., Frankland J.A., Garner P., Garnett J., Gribble S., Griffiths C., Grocock R., Gustafson E., Hammond S., Harley J.L., Hart E., Heath P.D., Ho T.P., Hopkins B., Horne J., Howden P.J., Huckle E., Hynds C., Johnson C., Johnson D., Kana A., Kay M., Kimberley A.M., Kershaw J.K., Kokkinaki M., Laird G.K., Lawlor S., Lee H.M., Leongamornlert D.A., Laird G., Lloyd C., Lloyd D.M., Loveland J., Lovell J., McLaren S., McLay K.E., McMurray A., Mashreghi-Mohammadi M., Matthews L., Milne S., Nickerson T., Nguyen M., Overton-Larty E., Palmer S.A., Pearce A.V., Peck A.I., Pelan S., Phillimore B., Porter K., Rice C.M., Rogosin A., Ross M.T., Sarafidou T., Sehra H.K., Shownkeen R., Skuce C.D., Smith M., Standring L., Sycamore N., Tester J., Thorpe A., Torcasso W., Tracey A., Tromans A., Tsolas J., Wall M., Walsh J., Wang H., Weinstock K., West A.P., Willey D.L., Whitehead S.L., Wilming L., Wray P.W., Young L., Chen Y., Lovering R.C., Moschonas N.K., Siebert R., Fechtel K., Bentley D., Durbin R.M., Hubbard T., Doucette-Stamm L., Beck S., Smith D.R., Rogers J. Nature 429:375-381(2004) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[3]	"Prediction of the coding sequences of unidentified human genes. XIX. The complete sequences of 100 new cDNA clones from brain which code for large proteins in vitro." Nagase T., Kikuno R., Hattori A., Kondo Y., Okumura K., Ohara O. DNA Res. 7:347-355(2000) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 1402-2136. Tissue: Brain.
[4]	"The full-ORF clone resource of the German cDNA consortium." Bechtel S., Rosenfelder H., Duda A., Schmidt C.P., Ernst U., Wellenreuther R., Mehrle A., Schuster C., Bahr A., Bloecker H., Heubner D., Hoerlein A., Michel G., Wedler H., Koehrer K., Ottenwaelder B., Poustka A., Wiemann S., Schupp I. BMC Genomics 8:399-399(2007) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 1665-2074. Tissue: Brain.
[5]	"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)." The MGC Project Team Genome Res. 14:2121-2127(2004) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 1809-2136. Tissue: Uterus.
[6]	"TET1, a member of a novel protein family, is fused to MLL in acute myeloid leukemia containing the t(10;11)(q22;q23)." Lorsbach R.B., Moore J., Mathew S., Raimondi S.C., Mukatira S.T., Downing J.R. Leukemia 17:637-641(2003) [PubMed] [Europe PMC] [Abstract] Cited for: CHROMOSOMAL TRANSLOCATION WITH MLL, TISSUE SPECIFICITY.
[7]	"The nuclear DNA base 5-hydroxymethylcytosine is present in Purkinje neurons and the brain." Kriaucionis S., Heintz N. Science 324:929-930(2009) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION.
[8]	"Conversion of 5-methylcytosine to 5-hydroxymethylcytosine in mammalian DNA by the MLL fusion partner TET1." Tahiliani M., Koh K.P., Shen Y., Pastor W.A., Bandukwala H., Brudno Y., Agarwal S., Iyer L.M., Liu D.R., Aravind L., Rao A. Science 324:930-935(2009) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION, CATALYTIC ACTIVITY, DNA-BINDING, COFACTOR, MUTAGENESIS OF HIS-1672 AND ASP-1674.
[9]	"Hydroxylation of 5-methylcytosine by TET1 promotes active DNA demethylation in the adult brain." Guo J.U., Su Y., Zhong C., Ming G.L., Song H. Cell 145:423-434(2011) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION IN DNA DEMETHYLATION, CATALYTIC ACTIVITY, MUTAGENESIS OF HIS-1672 AND ASP-1674.
[10]	"TET1 and hydroxymethylcytosine in transcription and DNA methylation fidelity." Williams K., Christensen J., Pedersen M.T., Johansen J.V., Cloos P.A., Rappsilber J., Helin K. Nature 473:343-348(2011) [PubMed] [Europe PMC] [Abstract] Cited for: INTERACTION WITH SIN3A.
[11]	"Tet proteins can convert 5-methylcytosine to 5-formylcytosine and 5-carboxylcytosine." Ito S., Shen L., Dai Q., Wu S.C., Collins L.B., Swenberg J.A., He C., Zhang Y. Science 333:1300-1303(2011) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION.
+	Additional computationally mapped references.

Cross-references

Sequence databases
EMBL GenBank DDBJ	AF430147 mRNA. Translation: AAM88301.1. AL513534, AL713888 Genomic DNA. Translation: CAH70220.1. AL713888, AL513534 Genomic DNA. Translation: CAI15118.1. AB051463 mRNA. Translation: BAB21767.1. AL713658 mRNA. Translation: CAD28467.3. Sequence problems. BC053905 mRNA. Translation: AAH53905.1.
IPI	IPI00303112.
RefSeq	NP_085128.2. NM_030625.2.
UniGene	Hs.567594. Hs.708977.
3D structure databases
ProteinModelPortal	Q8NFU7.
ModBase	Search...
Protein-protein interaction databases
STRING	9606.ENSP00000362748.
PTM databases
PhosphoSite	Q8NFU7.
Polymorphism databases
DMDM	115502139.
Proteomic databases
PaxDb	Q8NFU7.
PRIDE	Q8NFU7.
Protocols and materials databases
DNASU	80312.
StructuralBiologyKnowledgebase	Search...
Genome annotation databases
Ensembl	ENST00000373644; ENSP00000362748; ENSG00000138336.
GeneID	80312.
KEGG	hsa:80312.
UCSC	uc001jok.4. human.
Organism-specific databases
CTD	80312.
GeneCards	GC10P070320.
HGNC	HGNC:29484. TET1.
HPA	CAB014886. HPA019032.
MIM	607790. gene.
neXtProt	NX_Q8NFU7.
PharmGKB	PA162405605.
HUGE	Search...
GenAtlas	Search...
Phylogenomic databases
eggNOG	NOG76473.
HOGENOM	HOG000154549.
InParanoid	Q8NFU7.
KO	K13097.
OMA	FSWSPKT.
OrthoDB	EOG4HT8SM.
PhylomeDB	Q8NFU7.
Gene expression databases
Bgee	Q8NFU7.
CleanEx	HS_TET1.
Genevestigator	Q8NFU7.
GermOnline	ENSG00000138336. Homo sapiens.
Family and domain databases
InterPro	IPR024779. 2OGFeDO_nucleic_acid_mod. IPR002857. Znf_CXXC. [Graphical view]
Pfam	PF12851. Tet_JBP. 1 hit. PF02008. zf-CXXC. 1 hit. [Graphical view]
PROSITE	PS51058. ZF_CXXC. 1 hit. [Graphical view]
ProtoNet	Search...
Other
ChiTaRS	TET1. human.
GenomeRNAi	80312.
NextBio	70802.
SOURCE	Search...

Entry information

Entry name

TET1_HUMAN

Accession

Primary (citable) accession number: Q8NFU7
Secondary accession number(s): Q5VUP7 , Q7Z6B6, Q8TCR1, Q9C0I7

Entry history

Integrated into UniProtKB/Swiss-Prot:	October 3, 2006
Last sequence update:	October 3, 2006
Last modified:	May 1, 2013
This is version 80 of the entry and version 2 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program

Disclaimer

Any medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.