Distributive processing by the iron(II)/α-ketoglutarate-dependent catalytic domains of the TET enzymes is consistent with epigenetic roles for oxidized 5-methylcytosine bases.

Distributive processing by the iron(II)/α-ketoglutarate-dependent catalytic domains of the TET enzymes is consistent with epigenetic roles for oxidized 5-methylcytosine bases.

J Am Chem Soc. 2016 Jun 30;

Authors: Tamanaha EY, Guan S, Marks K, Saleh L

Abstract
The ten-eleven translocation (TET) proteins catalyze oxidation of 5-methylcytosine ((5m)C) residues in nucleic acids to 5-hydroxymethylcytosine ((5hm)C), 5-formylcytosine ((5f)C), and 5-carboxycytosine ((5ca)C). These nucleotide bases are implicated as intermediates on the path to active demethylation, but recent reports have suggested that they might have specific regulatory roles in their own right. In this study, we present kinetic evidence showing that the catalytic domains (CDs) of TET2 and TET1 from mouse, and their homolog from Naegleria gruberi, the full-length protein NgTET1, are distributive in both chemical and physical senses as they carry out successive oxidations of a single (5m)C and multiple (5m)C residues along a polymethylated DNA substrate. We present data showing that the enzyme neither retains (5hm)C/(5f)C intermediates of preceding oxidations nor slides along a DNA substrate (without releasing it) to process an adjacent (5m)C residue. These findings contradict a recent report, which claims that oxidation of (5m)C by CD of mouse TET2 is chemically processive (iterative) (Crawford et al. J. Am. Chem. Soc. Comm. 2016, 138, 730). We further elaborate that this distributive mechanism is maintained for TETs in two evolutionarily distant homologs and posit that this mode of function allows the introduction of (5m)C forms as epigenetic markers along the DNA.

PMID: 27362828 [PubMed - as supplied by publisher]

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