Citation

  • Authors: Pfaffeneder, T., Spada, F., Wagner, M., Brandmayr, C., Laube, S. K., Eisen, D., Truss, M., Steinbacher, J., Hackner, B., Kotljarova, O., Schuermann, D., Michalakis, S., Kosmatchev, O., Schiesser, S., Steigenberger, B., Raddaoui, N., Kashiwazaki, G., Muller, U., Spruijt, C. G., Vermeulen, M., Leonhardt, H., Schar, P., Muller, M., Carell, T.
  • Year: 2014
  • Journal: Nat Chem Biol 10 574-81
  • Applications: in vitro / DNA / jetPRIME
  • Cell type: HEK-293T
    Description: Human embryonic kidney Fibroblast
    Known as: HEK293T, 293T

Abstract

Ten eleven translocation (Tet) enzymes oxidize the epigenetically important DNA base 5-methylcytosine (mC) stepwise to 5-hydroxymethylcytosine (hmC), 5-formylcytosine and 5-carboxycytosine. It is currently unknown whether Tet-induced oxidation is limited to cytosine-derived nucleobases or whether other nucleobases are oxidized as well. We synthesized isotopologs of all major oxidized pyrimidine and purine bases and performed quantitative MS to show that Tet-induced oxidation is not limited to mC but that thymine is also a substrate that gives 5-hydroxymethyluracil (hmU) in mouse embryonic stem cells (mESCs). Using MS-based isotope tracing, we show that deamination of hmC does not contribute to the steady-state levels of hmU in mESCs. Protein pull-down experiments in combination with peptide tracing identifies hmU as a base that influences binding of chromatin remodeling proteins and transcription factors, suggesting that hmU has a specific function in stem cells besides triggering DNA repair.

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