Ponte Academic Journal Jul 2014, Volume 70, Issue 7 |
STRUCTURAL ANALYSIS OF THE EPIGENETIC CONTROLLER, HUMAN DNA METHYLTRANSFERASE I Author(s): C-H Hsu J. Ponte - Jul 2014 - Volume 70 - Issue 7 Abstract: DNA methylation, one of the epigenetic mechanisms, plays an important role in numerous biological functions in cells, from inhibition of cleavage by endonucleases to inhibition of transcription factor binding. The DNA methyltransferase I (DNMT1) protein represents a major DNA methyltransferase activity in human cells and is therefore a prominent target for environmental epigenetic control and experimental cancer therapies. However, there are only few available structural information and inhibitors as well as their high toxicity and low specificity have so far precluded their broad use in chemotherapy. Therefore, cloning and bacterial expression of several functional domains of DNMT1 were carried out for the structure determination by X-ray crystallography and NMR technique. One of the functional domain, DBD (the non-catalytic amino terminus of DNMT 1) binds a new protein, DMAP 1 (for DNMT 1 associated protein), and can mediate transcriptional repression. Bioinformatics, CD (circular dichroism) and NMR (nuclear magnetic resonance) spectroscopic approaches indicate this domain adopt the all helical topology. In addition, DBD showed DNA binding activity, and the responsible sequence was narrowed to about 80 amino acid residues involving the proliferating cell nuclear antigen (PCNA) binding motif. The DNA binding activity did not distinguish between DNA non-methylated and methylated states, but preferred to bind to the minor groove of AT-rich sequence. Furthermore, DNA binding activity of DBD may contributes to the localization of DNMT1 to AT-rich sequence such as satellite, Line 1, and the promoter of tissuespecific silent genes. The structural analysis of DBD of human DNMT1 could provide biological explanation for how the domain interacts with other regulation proteins onto the particular sites in genes expression, and give the structural view for specific inhibitor development.
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