DNA Methylation in Health and Disease
DNA methylation is a major epigenetic mechanism that regulates many cellular activities such as differentiation and genomic imprinting. The mammalian DNA methylation landscape is first established by de novo methyltransferases DNMT3A and DNMT3B, and maintained by DNMT1 during DNA replication. The most prevalent DNTM3A mutation, R882H, has been associated with global DNA hypomethylation in cells and greatly enhanced cell proliferation rate. This study addresses mechanisms that govern DNMT3A substrate specificity in the context of CpG and CpA and how the R882H mutation impacts structure and function. We also present structural evidence for how flanking nucleotides influence DNMT1 activity, towards elucidating atomic-level mechanisms that shape genomic methylation patterns and impairment in disease states.