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Sensors 2014, 14(1), 1195-1207; doi:10.3390/s140101195

Topoisomerase I as a Biomarker: Detection of Activity at the Single Molecule Level

1
Department of Pathology, Aarhus University Hospital, Aarhus C 8000, Denmark
2
Department of Molecular Biology and Genetics, Aarhus University, Aarhus C 8000, Denmark
3
Department of Biotechnology, National Institute of Pharmaceutical Education & Research (NIPER), Hajipur-844 101, Bihar, India
*
Author to whom correspondence should be addressed.
Received: 18 December 2013 / Revised: 3 January 2014 / Accepted: 7 January 2014 / Published: 10 January 2014
(This article belongs to the Special Issue Single Biomolecule Detection)
View Full-Text   |   Download PDF [370 KB, uploaded 21 June 2014]   |  

Abstract

Human topoisomerase I (hTopI) is an essential cellular enzyme. The enzyme is often upregulated in cancer cells, and it is a target for chemotherapeutic drugs of the camptothecin (CPT) family. Response to CPT-based treatment is dependent on hTopI activity, and reduction in activity, and mutations in hTopI have been reported to result in CPT resistance. Therefore, hTOPI gene copy number, mRNA level, protein amount, and enzyme activity have been studied to explain differences in cellular response to CPT. We show that Rolling Circle Enhanced Enzyme Activity Detection (REEAD), allowing measurement of hTopI cleavage-religation activity at the single molecule level, may be used to detect posttranslational enzymatic differences influencing CPT response. These differences cannot be detected by analysis of hTopI gene copy number, mRNA amount, or protein amount, and only become apparent upon measuring the activity of hTopI in the presence of CPT. Furthermore, we detected differences in the activity of the repair enzyme tyrosyl-DNA phosphodiesterase 1, which is involved in repair of hTopI-induced DNA damage. Since increased TDP1 activity can reduce cellular CPT sensitivity we suggest that a combined measurement of TDP1 activity and hTopI activity in presence of CPT will be the best determinant for CPT response. View Full-Text
Keywords: Topoisomerase-I; camptothecin; enzyme activity; biosensor; tyrosyl-DNA phosphodiesterase 1; single molecule; drug response; cancer Topoisomerase-I; camptothecin; enzyme activity; biosensor; tyrosyl-DNA phosphodiesterase 1; single molecule; drug response; cancer
This is an open access article distributed under the Creative Commons Attribution License (CC BY 3.0).

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MDPI and ACS Style

Proszek, J.; Roy, A.; Jakobsen, A.-K.; Frøhlich, R.; Knudsen, B.R.; Stougaard, M. Topoisomerase I as a Biomarker: Detection of Activity at the Single Molecule Level. Sensors 2014, 14, 1195-1207.

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