Structural basis for impairment of DNA methylation by the DNMT3A R882H mutation

Abstract

The DNA methyltransferase DNMT3A plays an important role in establishing the DNA methylation patterns during development and deregulation of DNMT3A is associated with hematological cancers, with the R882H mutation the most frequently occurring DNMT3A missense mutation in acute myeloid leukemia. Here, the authors present the crystal structures of wild-type and R882H DNMT3A in complex with different DNA substrates and explain why the R882H mutation compromises the enzymatic activity of DNMT3A.