Mediating and maintaining methylation while minimizing mutation: Recent advances on mammalian DNA methyltransferases

Mammalian genomes are methylated on carbon-5 of many cytosines, mostly in CpG dinucleotides. Methylation patterns are maintained during mitosis via DNMT1, and regulatory factors involved in processes that include histone modifications. Methylation in a sequence longer than CpG can influence the binding of sequence-specific transcription factors, thus affecting gene expression. 5-Methylcytosine deamination results in C-to-T transition. While some mutations are beneficial, most are not; so boosting C-to-T transitions can be dangerous. Given the role of DNMT3A in establishing de novo DNA methylation during development, it is this CpG methylation and deamination that provide the major mutagenic impetus in the DNMT3A gene itself, including the R882H dominant-negative substitution associated with two diseases: germline mutations in DNMT3A overgrowth syndrome, and somatic mutations in clonal hematopoiesis that can initiate acute myeloid leukemia. We discuss recent developments in therapeutics targeting DNMT1, the role of noncatalytic isoform DNMT3B3 in regulating de novo methylation by DNMT3A, and structural characterization of DNMT3A in various configurations.