Stalling of human DNA (cytosine-5) methyltransferase at single-strand conformers from a site of dynamic mutation

Journal of Molecular Biology
M R KhoS S Smith

Abstract

Single-strand conformers (SSCs) from the C-rich strand of the triplet repeat at the FMR-1 locus are rapidly and selectively methylated by the human DNA (cytosine-5) methyltransferase. The apparent affinity of the enzyme for the FMR-1 SSC is about tenfold higher than it is for a control Watson-Crick paired duplex. The de novo methylation rate for the SSC is over 150-fold higher than the de novo rate for the control duplex. Methylation of what is generally called a hemi-methylated duplex occurs with a rate enhancement of over 100-fold, while methylation of what can be viewed as a hemi-methylated FMR-1 SSC is actually slower than the de novo rate. The pronounced inhibition of the methyltransferase by the methylated SSC suggests that the enzyme has a higher affinity for the methylated product of its reaction with the SSC than it has for the unmethylated SSC substrate. Gel retardation studies show that the methyltransferase binds selectively to SSCs from the C-rich strand of the FMR-1 triplet repeat. This suggests a two-step stalling process in which the human methyltransferase first selectively methlyates and subsequently stalls at the C-rich strand SSC. Stalling may reflect the inability of the enzyme to release a DNA product that...Continue Reading

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Citations

Oct 26, 2005·Nucleic Acids Research·Taras ShevchukSteven S Smith
Jun 5, 2003·BMC Molecular Biology·Jean B MargotHeinrich Leonhardt
Sep 21, 2013·Nephrology, Dialysis, Transplantation : Official Publication of the European Dialysis and Transplant Association - European Renal Association·Björn Tampe, Michael Zeisberg
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Feb 15, 2005·Analytical Biochemistry·Yaroslav Buryanov, Taras Shevchuk
Aug 31, 2017·Biochemistry·Elisé P WrightZoë A E Waller

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