Tet methylcytosine dioxygenase 2 explained

Tet methylcytosine dioxygenase 2 (TET2) is a human gene.[1] It resides at chromosome 4q24, in a region showing recurrent microdeletions and copy-neutral loss of heterozygosity (CN-LOH) in patients with diverse myeloid malignancies.

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.[2] [3] In these two papers, Kriaucionis and Heintz provided evidence that a high abundance of 5hmC can be found in specific tissues and Tahiliani et al. 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),[4] [5] a positive global regulator of gene transcription that is named after its role cancer regulation. An explanation for protein function was provided in 2009 [6] 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,[7] although the evidence of an unusual form of DNA modification goes back to at least the mid 1980s.[8]

In two articles published back-to-back in Science journal in 2011, firstly[9] 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[10] 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).[11] [12] 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 demonstrated the activity for TDG as also excising the oxidation products of 5-methylcytosine. Furthermore, in the same year 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 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.[13] 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.[14] [15] [16] [17] [18] [19] [20] 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].[21] In mice the depletion of TET2 skewed the differentiation of haematopoietic precursors, as well as amplifying the rate of haematopoietic or progenitor cell renewal.[22] [23] [24] [25]

Somatic TET2 mutations are frequently observed in myelodysplastic syndromes (MDS), myeloproliferative neoplasms (MPN), MDS/MPN overlap syndromes including chronic myelomonocytic leukaemia (CMML), acute myeloid leukaemias (AML) and secondary AML (sAML).[26]

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.[27]

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.[28] 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.[29] 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.[30] Importantly, TET2 is mutated in a mutually exclusive manner with WT1, IDH1, and IDH2.[31] [32] TET2 can be recruited by WT1, a sequence-specific zinc finger transcription factor, to WT1-target genes, which it then activates by converting methylcytosine into 5-hydroxymethylcytosine at the genes’ promoters. Additionally, isocitrate dehydrogenases 1 and 2, encoded by IDH1 and IDH2, respectively, can inhibit the activity of TET proteins when present in mutant forms that produce the TET inhibitor D-2-hydroxyglutarate.[33] Together, WT1, IDH1/2 and TET2 define the WIT pathway in AML. The WIT pathway might also be more broadly involved in suppressing tumor formation, as a number of non-hematopoietic malignancies appear to harbor mutations of WIT genes in a non-exclusive manner.

Further reading

Notes and References

  1. Web site: Entrez Gene: Tet methylcytosine dioxygenase 1. 1 September 2012.
  2. Kriaucionis S, Heintz N . The nuclear DNA base 5-hydroxymethylcytosine is present in Purkinje neurons and the brain . Science . 324 . 5929 . 929–30 . May 2009 . 19372393 . 3263819 . 10.1126/science.1169786 . 2009Sci...324..929K .
  3. Tahiliani M, Koh KP, Shen Y, Pastor WA, Bandukwala H, Brudno Y, Agarwal S, Iyer LM, Liu DR, Aravind L, Rao A . 6 . Conversion of 5-methylcytosine to 5-hydroxymethylcytosine in mammalian DNA by MLL partner TET1 . Science . 324 . 5929 . 930–5 . May 2009 . 19372391 . 2715015 . 10.1126/science.1170116 . 2009Sci...324..930T .
  4. Lorsbach RB, Moore J, Mathew S, Raimondi SC, Mukatira ST, Downing JR . TET1, a member of a novel protein family, is fused to MLL in acute myeloid leukemia containing the t(10;11)(q22;q23) . Leukemia . 17 . 3 . 637–41 . March 2003 . 12646957 . 10.1038/sj.leu.2402834 . 1202064 .
  5. Ono R, Taki T, Taketani T, Taniwaki M, Kobayashi H, Hayashi Y . 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) . Cancer Research . 62 . 14 . 4075–80 . July 2002 . 12124344 .
  6. Tahiliani M, Koh KP, Shen Y, Pastor WA, Bandukwala H, Brudno Y, Agarwal S, Iyer LM, Liu DR, Aravind L, Rao A . 6 . Conversion of 5-methylcytosine to 5-hydroxymethylcytosine in mammalian DNA by MLL partner TET1 . Science . 324 . 5929 . 930–5 . May 2009 . 19372391 . 10.1126/science.1170116 . 2715015 . 2009Sci...324..930T .
  7. Gommers-Ampt JH, Van Leeuwen F, de Beer AL, Vliegenthart JF, Dizdaroglu M, Kowalak JA, Crain PF, Borst P . 6 . beta-D-glucosyl-hydroxymethyluracil: a novel modified base present in the DNA of the parasitic protozoan T. brucei . Cell . 75 . 6 . 1129–36 . December 1993 . 8261512 . 10.1016/0092-8674(93)90322-h . 1874/5219 . 24801094 . free .
  8. Bernards A, van Harten-Loosbroek N, Borst P . Modification of telomeric DNA in Trypanosoma brucei; a role in antigenic variation? . Nucleic Acids Research . 12 . 10 . 4153–70 . May 1984 . 6328412 . 10.1093/nar/12.10.4153 . 318823 .
  9. He YF, Li BZ, Li Z, Liu P, Wang Y, Tang Q, Ding J, Jia Y, Chen Z, Li L, Sun Y, Li X, Dai Q, Song CX, Zhang K, He C, Xu GL . 6 . Tet-mediated formation of 5-carboxylcytosine and its excision by TDG in mammalian DNA . Science . 333 . 6047 . 1303–7 . September 2011 . 21817016 . 3462231 . 10.1126/science.1210944 . 2011Sci...333.1303H .
  10. Ito S, Shen L, Dai Q, Wu SC, Collins LB, Swenberg JA, He C, Zhang Y . 6 . Tet proteins can convert 5-methylcytosine to 5-formylcytosine and 5-carboxylcytosine . Science . 333 . 6047 . 1300–3 . September 2011 . 21778364 . 3495246 . 10.1126/science.1210597 . 2011Sci...333.1300I .
  11. Maiti A, Drohat AC . Thymine DNA glycosylase can rapidly excise 5-formylcytosine and 5-carboxylcytosine: potential implications for active demethylation of CpG sites . The Journal of Biological Chemistry . 286 . 41 . 35334–8 . October 2011 . 21862836 . 10.1074/jbc.c111.284620 . 3195571 . free .
  12. Weber AR, Krawczyk C, Robertson AB, Kuśnierczyk A, Vågbø CB, Schuermann D, Klungland A, Schär P . 6 . Biochemical reconstitution of TET1-TDG-BER-dependent active DNA demethylation reveals a highly coordinated mechanism . Nature Communications . 7 . 1 . 10806 . March 2016 . 26932196 . 10.1038/ncomms10806 . 4778062 . 2016NatCo...710806W . free .
  13. Langemeijer SM, Kuiper RP, Berends M, Knops R, Aslanyan MG, Massop M, Stevens-Linders E, van Hoogen P, van Kessel AG, Raymakers RA, Kamping EJ, Verhoef GE, Verburgh E, Hagemeijer A, Vandenberghe P, de Witte T, van der Reijden BA, Jansen JH . 6 . Acquired mutations in TET2 are common in myelodysplastic syndromes . Nature Genetics . 41 . 7 . 838–42 . July 2009 . 19483684 . 10.1038/ng.391 . 9859570 .
  14. Delhommeau F, Dupont S, Della Valle V, James C, Trannoy S, Massé A, Kosmider O, Le Couedic JP, Robert F, Alberdi A, Lécluse Y, Plo I, Dreyfus FJ, Marzac C, Casadevall N, Lacombe C, Romana SP, Dessen P, Soulier J, Viguié F, Fontenay M, Vainchenker W, Bernard OA . 6 . Mutation in TET2 in myeloid cancers . The New England Journal of Medicine . 360 . 22 . 2289–301 . May 2009 . 19474426 . 10.1056/NEJMoa0810069 . free .
  15. Langemeijer SM, Kuiper RP, Berends M, Knops R, Aslanyan MG, Massop M, Stevens-Linders E, van Hoogen P, van Kessel AG, Raymakers RA, Kamping EJ, Verhoef GE, Verburgh E, Hagemeijer A, Vandenberghe P, de Witte T, van der Reijden BA, Jansen JH . 6 . Acquired mutations in TET2 are common in myelodysplastic syndromes . Nature Genetics . 41 . 7 . 838–42 . July 2009 . 19483684 . 10.1038/ng.391 . 9859570 .
  16. Abdel-Wahab O, Mullally A, Hedvat C, Garcia-Manero G, Patel J, Wadleigh M, Malinge S, Yao J, Kilpivaara O, Bhat R, Huberman K, Thomas S, Dolgalev I, Heguy A, Paietta E, Le Beau MM, Beran M, Tallman MS, Ebert BL, Kantarjian HM, Stone RM, Gilliland DG, Crispino JD, Levine RL . 6 . Genetic characterization of TET1, TET2, and TET3 alterations in myeloid malignancies . Blood . 114 . 1 . 144–7 . July 2009 . 19420352 . 10.1182/blood-2009-03-210039 . 2710942 .
  17. Jankowska AM, Szpurka H, Tiu RV, Makishima H, Afable M, Huh J, O'Keefe CL, Ganetzky R, McDevitt MA, Maciejewski JP . 6 . Loss of heterozygosity 4q24 and TET2 mutations associated with myelodysplastic/myeloproliferative neoplasms . Blood . 113 . 25 . 6403–10 . June 2009 . 19372255 . 10.1182/blood-2009-02-205690 . 2710933 .
  18. Tefferi A, Pardanani A, Lim KH, Abdel-Wahab O, Lasho TL, Patel J, Gangat N, Finke CM, Schwager S, Mullally A, Li CY, Hanson CA, Mesa R, Bernard O, Delhommeau F, Vainchenker W, Gilliland DG, Levine RL . 6 . TET2 mutations and their clinical correlates in polycythemia vera, essential thrombocythemia and myelofibrosis . Leukemia . 23 . 5 . 905–11 . May 2009 . 19262601 . 4654629 . 10.1038/leu.2009.47 .
  19. Tefferi A, Levine RL, Lim KH, Abdel-Wahab O, Lasho TL, Patel J, Finke CM, Mullally A, Li CY, Pardanani A, Gilliland DG . 6 . Frequent TET2 mutations in systemic mastocytosis: clinical, KITD816V and FIP1L1-PDGFRA correlates . Leukemia . 23 . 5 . 900–4 . May 2009 . 19262599 . 10.1038/leu.2009.37 . 4654631 . free .
  20. Tefferi A, Lim KH, Abdel-Wahab O, Lasho TL, Patel J, Patnaik MM, Hanson CA, Pardanani A, Gilliland DG, Levine RL . 6 . Detection of mutant TET2 in myeloid malignancies other than myeloproliferative neoplasms: CMML, MDS, MDS/MPN and AML . Leukemia . 23 . 7 . 1343–5 . July 2009 . 19295549 . 10.1038/leu.2009.59 . 4654626 . free .
  21. Ko M, Huang Y, Jankowska AM, Pape UJ, Tahiliani M, Bandukwala HS, An J, Lamperti ED, Koh KP, Ganetzky R, Liu XS, Aravind L, Agarwal S, Maciejewski JP, Rao A . 6 . Impaired hydroxylation of 5-methylcytosine in myeloid cancers with mutant TET2 . Nature . 468 . 7325 . 839–43 . December 2010 . 21057493 . 3003755 . 10.1038/nature09586 . 2010Natur.468..839K .
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