New publication in "Scientific Reports"

The R882H mutation in the DNMT3A DNA methyltransferase occurs frequently in AML and it has an early role in tumorigenesis. The R882H mutation is located at one of the subunit interface of the DNMT3A tetramer, which also forms the DNA binding site of DNMT3A. However, the pathogenic mechanism of the R882H mutation is not completely understood. Recently it has been reported that the R882H mutation has a dominant negative effect in complex with wildtype DNMT3A subunits (Russler-Germain et al., 2014, Cancer Cell 25:442-454). To gain insight into this mechanism, we aimed to investigate the structural and functional details of this proposed mechanism and studied mixed DNMT3A complexes containing wildtype and R882H subunits. However as described in this publication in Scientific Reports, we did not observe a reduction in activity which would be indicative of a dominant negative effect of the mutation. Our data suggest that the DNMT3A R882H mutation does not cause a dominant negative effect in mixed heterotetramer.