Figure 7.

Model of DNMT3A regulation by oligomer formation and the influence of R882H and DNMT3L. DNMT3A exists in an equilibrium between very large oligomeric multimers and smaller complexes about the size of a tetramer. Here, large oligomeric DNMT3A species are significantly less active than smaller complexes. The R882H hot spot mutation found in leukemia exerts its dominant-negative behavior in part by binding WT DNMT3A and shifting the distribution of DNMT3A complexes from smaller, more active tetramers to larger oligomers with low activity. DNMT3L activates DNMT3A by breaking up large oligomers into smaller complexes.