Ubc9 is an E2-conjugating enzyme required for sumoylation and has been 
implicated in regulating several critical cellular pathways. We have shown 
previously that Ubc9 is important for sumoylation and nucleolar delocalization 
of topoisomerase (topo) I in response to topo I inhibitors such as topotecan. 
However, the role for Ubc9 in tumor drug responsiveness is not clear. In this 
study, we found that although MCF7 cells expressing a Ubc9 dominant-negative 
mutant (Ubc9-DN) display decreased activity of topo I, these cells are more 
sensitive to the topo I inhibitor topotecan and other anticancer agents such as 
VM-26 and cisplatin. In addition, we found that alteration of Ubc9 expression 
correlates with drug responsiveness in tumor cell lines. To understand possible 
mechanisms of Ubc9-associated drug responsiveness, we examined several proteins 
that have been shown to interact with Ubc9 and that may be involved in drug 
responsiveness. One such protein is Daxx, which is a Fas-associated protein that 
plays a role in Fas-mediated apoptosis by participating in a caspase-independent 
pathway through activation of apoptosis signal-regulating kinase 1 and c-Jun 
NH(2)-terminal kinase. We found that cells expressing Ubc9-DN accumulate more 
cytoplasmic Daxx than the control cells. Because cytoplasmic Daxx is believed to 
participate in cellular apoptosis, we suggest that the interaction of Ubc9 with 
Daxx and subsequent alteration in the subcellular localization of Daxx may 
contribute to the increased sensitivity to anticancer drugs in the cells 
expressing Ubc9-DN. Finally, we found that overexpression of Daxx sensitizes 
cells to anticancer drugs possibly in part through alterations of the ratio of 
cytoplasmic and nuclear Daxx. Together, our results suggest a role for Ubc9 in 
tumor drug responsiveness.