New publication in "Nucleic Acids Research"
Several recent studies reported that the R882H mutation in the DNMT3A DNA methyltransferase occurs frequently in AML and it has an early role in tumorigenesis, but its exact tumor promoting mechanism is not known. DNMT3A methylates DNA at CG sites, but its activity is strongly dependent on the surrounding DNA sequence context. In this work we show that the R882H mutation causes a pronounced shift in the flanking sequence preferences of DNMT3A, indicating that some CG sites are very poorly methylated by the mutant, while others are methylated even better by the mutant than by wildtype. Our data expand the model of the potential carcinogenic effect of the R882H mutation by showing CpG site specific activity changes. This result suggests that R882 is involved in contacts of DNMT3A to the DNA backbone, which mediate an indirect readout of flanking sequence preferences. This finding may explain the particular enrichment of the R882H mutation in cancer patients.
|Prof. Dr. Albert Jeltsch