TET2 is a protein implicated in several myeloproliferative disorders, including acute myeloid leukemia. TET2 catalyzes a stepwise oxidation from 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC) to 5-formylcytosine (5fC) to 5-carboxylcytosine (5caC). Experimental investigation of TET2 activity with various DNA, RNA and DNA-RNA substrates indicate that all-DNA strands were preferred over either dsDNA or ssDNA with a corresponding ribo-5mC target base, which showed a significant reduction in activity. Molecular dynamics (MD) simulations have been performed to investigate the impact that RNA’s 2’ hydroxyl at the target position of the DNA strand complexed with TET2 in both single-stranded and double-stranded contexts. These analyses reveal significant structural and dynamical changes between the DNA-only backbone and the mixed DNA-RNA backbone, which may impact the oxidation of 5mC, and provide an explanation for the differences in stalling behavior seen experimentally.

Computational investigation of TET2 activity on RNA-containing substrates

2019 Spring National Meeting

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