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- W3049678069 abstract "DNA methylation is an epigenetic modification that is nearly ubiquitous.Eukaryotic DNA methylation contributes to the regulation of gene expression andmaintaining genome integrity. In mammals, DNA methylation occurs primarily onthe C5 carbon of cytosine in a CpG dinucleotide context and is catalyzed by theDNA methyltransferases, DNMT1, DNMT3A and DNMT3B. While dnmt3aand dnmt3b genes are highlyhomologous, the enzymes have distinct functions. Some previous reportssuggested differences in the enzymatic behavior of DNMT3A and 3B, which couldaffect their biological roles. The goal of my thesis work was to characterize kineticsmechanisms of DNMT3A and 3B, and to identify the similarities and differencesin their catalytic properties that contribute to their distinct biologicalfunctions. Given the sequence similarity between the enzymes, we asked whetherDNMT3B was kinetically similar to DNMT3A. In a series of experiments designedto distinguish between various kinetics mechanisms, we reported that unlikeDNMT3A, DNMT3B methylated tandem CpG on DNA in a processive manner. We alsoreported that the disruption of the R-D interface, critical for thecooperativity of DNMT3A, had no effect on DNMT3B activity, supporting thenon-cooperative mechanism of this enzyme. DNMT3A is frequently mutated in numerous cancers. Acute Myeloid Leukemia(AML) is a malignancy of hematopoietic stem cells in which numerous patientsexhibit a high frequency of the heterozygous somatic mutation Arg882His inDNMT3A. Through thorough consensus motif building, we discovered a strongsimilarity in CpG flanking sequence preference between DNMT3A Arg882His variantand DNMT3B enzyme. Moreover, we found that the variant enzyme has the same kineticsmechanism as DNMT3B, indicating a gain-of-function effect caused by themutation. This change is significant because the variant enzyme can aberrantlymethylate DNMT3B targets in AML cells and effect global gene expression. In particular,given that DNMT3B has been shown to have oncogenic properties, this suggeststhat the Arg882His variant can acquire similar oncogenic properties and driveAML development.Taken together, my thesis work provides novel insights into therelationship between the biochemical properties and the biological functions ofDNMT3A and 3B." @default.
- W3049678069 created "2020-08-21" @default.
- W3049678069 creator A5061457770 @default.
- W3049678069 date "2020-08-14" @default.
- W3049678069 modified "2023-09-27" @default.
- W3049678069 title "Biochemical Investigation of the de novo DNA Methyltransferases DNMT3A and DNMT3B" @default.
- W3049678069 doi "https://doi.org/10.25394/pgs.12805529.v1" @default.
- W3049678069 hasPublicationYear "2020" @default.
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