The DNA binding and 3'-end preferential activity of human tyrosyl-DNA phosphodiesterase.

Nucleic Acids Research
Thomas S DexheimerYves Pommier

Abstract

Human tyrosyl-DNA phosphodiesterase (Tdp1) processes 3'-blocking lesions, predominantly 3'-phosphotyrosyl bonds resulting from the trapping of topoisomerase I (Top1) cleavage complexes. The controversial ability of yeast Tdp1 to hydrolyze 5'-phosphotyrosyl linkage between topoisomerase II (Top2) and DNA raises the question whether human Tdp1 possesses 5'-end processing activity. Here we characterize the end-binding and cleavage preference of human Tdp1 using single-stranded 5'- and 3'-fluorescein-labeled oligonucleotides. We establish 3'-fluorescein as an efficient surrogate substrate for human Tdp1, provided it is attached to the DNA by a phosphodiester (but not a phosphorothioate) linkage. We demonstrate that human Tdp1 lacks the ability to hydrolyze a phosphodiester linked 5'-fluorescein. Using both fluorescence anisotropy and time-resolved fluorescence quenching techniques, we also show the preferential binding of human Tdp1 to the 3'-end. However, DNA binding competition experiments indicate that human Tdp1 binding is dependent on DNA length rather than number of DNA ends. Lastly, using surface plasmon resonance, we show that human Tdp1 selectively binds the 3'-end of DNA. Together, our results suggest human Tdp1 may act u...Continue Reading

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Citations

Mar 29, 2013·Journal of Molecular Histology·Hok Khim FamGlenda Hendson
May 23, 2013·Biosensors & Bioelectronics·Pia W JensenMagnus Stougaard
Mar 15, 2012·Nature Communications·Jessica J R HudsonSherif F El-Khamisy
Feb 5, 2014·Nucleic Acids Research·Benu Brata DasYves Pommier
Oct 22, 2014·Proceedings of the National Academy of Sciences of the United States of America·DongYu GuoHoward A Nash
Aug 17, 2011·Expert Opinion on Therapeutic Patents·Shar-yin N HuangChristophe Marchand
Dec 14, 2011·Journal of Molecular Biology·Stefan GajewskiRobert C A M van Waardenburg
Apr 6, 2011·The Biochemical Journal·Heidrun Interthal, James J Champoux
Apr 24, 2012·Biochimie·Natalia A LebedevaOlga I Lavrik
May 27, 2014·DNA Repair·Yves PommierChristophe Marchand
Jan 4, 2018·Nature Communications·Fiona J FlettJulia M Richardson
Sep 8, 2018·Journal of Enzyme Inhibition and Medicinal Chemistry·Anastasia O KomarovaOlga I Lavrik
Jan 15, 2016·Bioorganicheskaia khimiia·N I RechkunovaO I Lavrik
Dec 14, 2018·Anti-cancer Agents in Medicinal Chemistry·Evgenii S MozhaitsevOlga I Lavrik
Jul 16, 2014·Molecular Cancer Therapeutics·Christophe MarchandYves Pommier

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Methods Mentioned

BETA
electrophoresis
Fluorescence
chip
chips

Software Mentioned

BiaEvaluation
PicoQuant
FluoFit

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