Tet methylcytosine dioxygenase 2
TET2 | |||
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Gene ontology | |||
Molecular function | |||
Cellular component | |||
Biological process | |||
Sources:Amigo / QuickGO |
Ensembl | |||||||||
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UniProt | |||||||||
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RefSeq (protein) | |||||||||
Location (UCSC) | Chr 4: 105.15 – 105.28 Mb | Chr 3: 133.17 – 133.25 Mb | |||||||
PubMed search | [3] | [4] |
View/Edit Human | View/Edit Mouse |
Tet methylcytosine dioxygenase 2 (TET2) is a human
Function
TET2 encodes a protein that catalyzes the conversion of the modified DNA base methylcytosine to 5-hydroxymethylcytosine.
The first mechanistic reports showed tissue-specific accumulation of 5-hydroxymethylcytosine (5hmC) and the conversion of 5mC to 5hmC by TET1 in humans in 2009.[6][7] In these two papers, Kriaucionis and Heintz [6] provided evidence that a high abundance of 5hmC can be found in specific tissues and Tahiliani et al.[7] demonstrated the TET1-dependent conversion of 5mC to 5hmC. A role for TET1 in cancer was reported in 2003 showing that it acted as a complex with MLL (myeloid/lymphoid or mixed-lineage leukaemia 1) (KMT2A),[8][9] a positive global regulator of gene transcription that is named after its role cancer regulation. An explanation for protein function was provided in 2009 [10] via computational search for enzymes that could modify 5mC. At this time, methylation was known to be crucial for gene silencing, mammalian development, and retrotransposon silencing. The mammalian TET proteins were found to be orthologues of Trypanosoma brucei base J-binding protein 1 (JBP1) and JBP2. Base J was the first hypermodified base that was known in eukaryotic DNA and had been found in T. brucei DNA in the early 1990s,[11] although the evidence of an unusual form of DNA modification goes back to at least the mid 1980s.[12]
In two articles published back-to-back in Science journal in 2011, firstly[13] it was demonstrated that (1) TET converts 5mC to 5fC and 5caC, and (2) 5fC and 5caC are both present in mouse embryonic stem cells and organs, and secondly[14] that (1) TET converts 5mC and 5hmC to 5caC, (2) the 5caC can then be excised by thymine DNA glycosylase (TDG), and (3) depleting TDG causes 5caC accumulation in mouse embryonic stem cells.
In general terms, DNA methylation causes specific sequences to become inaccessible for gene expression. The process of demethylation is initiated through modification of the 5mC to 5hmC, 5fC, etc. To return to the unmodified form of cytosine (C), the site is targeted for TDG-dependent base excision repair (TET–TDG–BER).[13][15][16] The “thymine” in TDG (thymine DNA glycosylase) might be considered a misnomer; TDG was previously known for removing thymine moieties from G/T mismatches.
The process involves hydrolysing the carbon-nitrogen bond between the sugar-phosphate DNA backbone and the mismatched thymine. Only in 2011, two publications [13][14] demonstrated the activity for TDG as also excising the oxidation products of 5-methylcytosine. Furthermore, in the same year [15] it was shown that TDG excises both 5fC and 5caC. The site left behind remains abasic until it is repaired by the base excision repair system. The biochemical process was further described in 2016 [16] by evidence of base excision repair coupled with TET and TDG.
In simple terms, TET–TDG–BER produces demethylation; TET proteins oxidise 5mC to create the substrate for TDG-dependent excision. Base excision repair then replaces 5mC with C.
Clinical significance
The most striking outcome of aberrant TET activity is its association with the development of cancer.
Mutations in this gene were first identified in myeloid neoplasms with deletion or uniparental disomy at 4q24.[17] TET2 may also be a candidate for active DNA demethylation, the catalytic removal of the methyl group added to the fifth carbon on the cytosine base.
Damaging variants in TET2 were attributed as the cause of several myeloid malignancies around the same time as the protein’s function was reported for TET-dependent oxidation.[18][19][20][21][22][23][24] Not only were damaging TET2 mutations found in disease, but the levels of 5hmC were also affected, linking the molecular mechanism of impaired demethylation with disease [75].[25] In mice the depletion of TET2 skewed the differentiation of haematopoietic precursors,[25] as well as amplifying the rate of haematopoietic or progenitor cell renewal.[26][27][28][29]
TET2 mutations have prognostic value in cytogenetically normal acute myeloid leukemia (CN-AML). "Nonsense" and "frameshift" mutations in this gene are associated with poor outcome on standard therapies in this otherwise favorable-risk patient subset.[31]
Loss-of-function TET2 mutations may also have a possible causal role in atherogenesis as reported by Jaiswal S. et al, as a consequence of clonal hematopoiesis.[32] Loss-of-function due to somatic variants are frequently reported in cancer, however homozygous germline loss-of-function has been shown in humans, causing childhood immunodeficiency and lymphoma.[33] The phenotype of immunodeficiency, autoimmunity and lymphoproliferation highlights requisite roles of TET2 in the human immune system.
WIT pathway
TET2 is mutated in 7%–23% of acute myeloid leukemia (AML) patients.
References
- ^ a b c GRCh38: Ensembl release 89: ENSG00000168769 – Ensembl, May 2017
- ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000040943 – Ensembl, May 2017
- ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ "Entrez Gene: Tet methylcytosine dioxygenase 1". Retrieved 1 September 2012.
- ^ PMID 19372393.
- ^ PMID 19372391.
- S2CID 1202064.
- PMID 12124344.
- PMID 19372391.
- S2CID 24801094.
- PMID 6328412.
- ^ PMID 21817016.
- ^ PMID 21778364.
- ^ PMID 21862836.
- ^ PMID 26932196.
- S2CID 9859570.
- PMID 19474426.
- S2CID 9859570.
- PMID 19420352.
- PMID 19372255.
- PMID 19262601.
- PMID 19262599.
- PMID 19295549.
- ^ PMID 21057493.
- PMID 21723200.
- PMID 21723201.
- PMID 21873190.
- PMID 21803851.
- PMID 21057493.
- PMID 21343549.
- PMID 28636844.
- S2CID 219564194.
- ^ PMID 25699704.
- PMID 25482556.
- ^ PMID 25601757.
- PMID 32777735.
Further reading
- Langemeijer SM, Kuiper RP, Berends M, Knops R, Aslanyan MG, Massop M, et al. (July 2009). "Acquired mutations in TET2 are common in myelodysplastic syndromes". Nature Genetics. 41 (7): 838–42. S2CID 9859570.
- Ko M, Huang Y, Jankowska AM, Pape UJ, Tahiliani M, Bandukwala HS, et al. (December 2010). "Impaired hydroxylation of 5-methylcytosine in myeloid cancers with mutant TET2". Nature. 468 (7325): 839–43. PMID 21057493.
- Metzeler KH, Maharry K, Radmacher MD, Mrózek K, Margeson D, Becker H, et al. (April 2011). "TET2 mutations improve the new European LeukemiaNet risk classification of acute myeloid leukemia: a Cancer and Leukemia Group B study". Journal of Clinical Oncology. 29 (10): 1373–81. PMID 21343549.