HTLV-1 Tax Oncoprotein Binds to DNA Topoisomerase I and Inhibits Its Catalytic Activity

Abstract

HTLV-1 Tax oncoprotein exerts pleiotropic effects on cellular regulatory systems, such as transcription and the cell cycle, through the interaction with various cellular factors. During our search for additional cellular targets of Tax using a yeast two-hybrid screening system, we isolated a cDNA encoding human DNA topoisomerase I. Tax was demonstrated to bind to topoisomerase I in vitro, and the Tax-topoisomerase I complex was also detected in HTLV-1-infected T-cells by immunoprecipitation. Furthermore, Tax inhibited the catalytic activity of topoisomerase I as measured by relaxation of supercoiled DNA, although complete inhibition was not observed under the conditions used. The binding of topoisomerase I to DNA was inhibited by the addition of the wild type of Tax but not by a mutant of Tax that cannot bind to topoisomerase I. Consistent with these observations, expression of Tax induced an in vivo reduction of the covalent association of topoisomerase I with chromosomal DNA, which accumulates in the presence of camptothecin. These results suggest that Tax has a novel potential to affect various cellular processes such as transcription and maintenance of genomic stability, in which DNA topoisomerase I is involved.