UniProt release 15.4
Published June 16, 2009
Dioxygenases: from antigenic variation to myeloid malignacies
Beta-D-glucopyranosyloxymethyluracil, also called base J, was the first hypermodified base to be identified in eukaryotic DNA, in 1993, in the nucleus of Trypanosoma brucei. Base J is shown to be present in all kinetoplastids analyzed, in the related marine flagellate Diplonema and in Euglena gracilis, a unicellular alga closely related to the Kinetoplastida (see review). Base J was not only absent in a variety of other protozoa, fungi and vertebrates, but most organisms lacking base J contain DNA glycosylases attacking hydroxymethyldeoxyuridine (HOMedU), thus actively preventing the appearance of this intermediate of base J synthesis. Mammals even contain a highly active dedicated HOMedU glycosylase.
The biosynthesis of base J has been characterized. It requires 2 dioxygenases: JBP1 and JBP2. But the precise function of this DNA modification is not clear. It seems to play a role in Trypanosoma or Leishmania antigenic variation. It was first suspected to be involved in gene silencing, but this hypothesis lacks support. A current idea is that it may regulate homologous recombination at telomeres where most genes encoding Variant Surface Glycoproteins (VSG) are located.
Although the existence of such a complex DNA modification seemed unlikely in vertebrates, Tahiliani et al. (2009) performed a computational search and found JBP homologs throughout metazoans, including man where 3 homologs - TET1, TET2, TET3 - were identified. Human TET1 was unambiguously shown to be able to catalyze the conversion from 5-methylcytosine to 5-hydroxymethylcytosine (hmC). Was it just a pure exercise in style? Actually not. HmC is present in mouse embryonic stem cells. Moreover it appears to be quite abundant in mouse brain, where it constitutes up to 0.6% of total nucleotides in Purkinje cells and 0.2% in granule cells (Kriaucionis and Heintz, 2009).
Human TET1 has been known since 2002 to be involved in some acute leukemias, where it plays the role of the fusion partner of MLL in the translocation t(10;11)(q22;q23) (Ono et al., 2002). In the first months of 2009, several articles pointed at TET2 mutations that contribute to pathogenesis of a wide spectrum of myeloid malignancies, including myelodysplastic syndromes, myeloproliferative disorders, acute myeloid and chronic myelomonocytic leukemias.
A new exciting area of investigation is now open to understand the physiological function of TET/JBP family members, which may be quite crucial in view of the dramatic consequences of their mutation. As of this release, the manually annotated protein sequences of these enzymes are available from UniProtKB/Swiss-Prot: JBP1, including Trypanosoma cruzi isoenzymes JBP1A and JBP1B, JBP2, TET1, TET2 and TET3.
Changes concerning cross-references to LinkHub
Cross-references to LinkHub have been removed.
Changes concerning keywords
Changes in subcellular location controlled vocabulary
New subcellular locations:
- Mitosome envelope
- Mitosome inner membrane
- Mitosome intermembrane space
- Mitosome matrix
- Mitosome membrane
- Mitosome outer membrane
- Spore polar tube
Modified subcellular locations:
- Host intracytoplasmic membrane -> Host endomembrane system
- Intracytoplasmic membrane -> Endomembrane system