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- W3176169807 abstract "Mammalian DNA methylation is an important epigenetic mechanism crucial for gene silencing and imprinting, X-inactivation, genome stability, and cell fate determination. It is established mainly at CpG dinucleotides by de novo methyltransferases DNMT3A and DNMT3B, and subsequently maintained by DNA methyltransferase 1 (DNMT1) in a replication-dependent manner. Deregulation of this process is implicated in various diseases, notably cancer. However, the mechanisms underlying DNMT3 substrate recognition and enzymatic specificity remain elusive. We determined the crystal structure of the DNMT3A – DNMT3L tetramer in complex with a DNA substrate containing two target sites separated by fourteen base pairs. Structural analysis of the DNMT3A – DNMT3L – DNA complex reveals that the two DNMT3A monomers simultaneously attack the two target sites, supporting the notion that DNMT3A homodimer can co-methylate two adjacent CpG dinucleotides in one DNA-binding event. Importantly, we identified that a residue from the target recognition domain makes crucial contacts with CpG, ensuring DNMT3A enzymatic preference towards CpG sites in cells. Mutational, enzymatic and cellular analyses further demonstrate that the hematological cancer-associated somatic mutations of the substrate-binding residues decrease DNMT3A activity, induce CpG hypomethylation, and promote transformation of hematopoietic cells. Together, our study reveals the mechanistic basis for DNMT3A-mediated DNA methylation. Support or Funding Information Sidney Kimmel Foundation for Cancer Research;March of Dimes Foundation (1-FY15-345);National Institute of Health (1R35GM119721) This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal." @default.
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- W3176169807 date "2018-04-01" @default.
- W3176169807 modified "2023-09-23" @default.
- W3176169807 title "Structure and mechanism of DNMT3A‐mediated DNA methylation" @default.
- W3176169807 doi "https://doi.org/10.1096/fasebj.2018.32.1_supplement.787.8" @default.
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