The extreme C-terminus of human Topoisomerase IΙ alpha defines a novel bi-modular DNA tether essential for the formation of mitotic chromosomes.

Abstract

Topoisomerase II is the target of an important class of anti-cancer drugs, but tumor cells can become resistant by reducing the association of the enzyme with chromosomes. We have determined the mechanism of Topo IIA recruitment to chromatin and provide new insight into the formation of mitotic chromosomes. We describe the first example of what is likely to be a widespread mechanism for recruitment of chromosomal proteins involving a bi-modular element consisting of an NLS and an associated DNA tether. Catalytically dead Topo IIA is successfully targeted to chromatin, but both the catalytic activity and the bi-modular targeting element are essential for mitotic chromosome formation. Because reduced strand passage activity protects cells from Topo IIA-targeted drugs, it is likely that mutations in the bi-modular element would lead to drug-resistance.