Published in

Portland Press, Bioscience Reports, 2(33), 2013

DOI: 10.1042/bsr20120118

Links

Tools

Export citation

Search in Google Scholar

A small organic compound enhances the religation reaction of human topoisomerase I and identifies crucial elements for the religation mechanism

Journal article published in 2013 by Barbara Arnò, Andrea Coletta ORCID, Cinzia Tesauro, Laura Zuccaro, Paola Fiorani, Sara Lentini, Pierluca Galloni ORCID, Valeria Conte, Barbara Floris, Alessandro Desideri
This paper is made freely available by the publisher.
This paper is made freely available by the publisher.

Full text: Download

Red circle
Preprint: archiving forbidden
Green circle
Postprint: archiving allowed
Upload
Green circle
Published version: archiving allowed
Upload
Policy details
Data provided by SHERPA/RoMEO

Abstract

The different steps of the human Top1 (topoisomerase I) catalytic cycle have been analysed in the presence of a pentacyclic-diquinoid synthetic compound. The experiments indicate that it efficiently inhibits the cleavage step of the enzyme reaction, fitting well into the catalytic site. Surprisingly the compound, when incubated with the binary topoisomerase–DNA cleaved complex, helps the enzyme to remove itself from the cleaved DNA and close the DNA gap, increasing the religation rate. The compound also induces the religation of the stalled enzyme–CPT (camptothecin)–DNA ternary complex. Analysis of the molecule docked over the binary complex, together with its chemical properties, suggests that the religation enhancement is due to the presence on the compound of two oxygen atoms that act as hydrogen acceptors. This property facilitates the deprotonation of the 5′ DNA end, suggesting that this is the limiting step in the topoisomerase religation mechanism.