Interaction between glucose-regulated destruction domain of DNA topoisomerase IIα and MPN domain of Jab1/CSN5

Abstract

DNA topoisomerase (topo) IIα an essential enzyme for cell proliferation, is targeted to a proteasome-dependent degradation pathway when human tumor cells are glucose-starved. Here we show that the topo IIα destabilization depends on the newly identified domain, GRDD (glucose-regulated destruction domain), which was mapped to the N-terminal 70-170 amino acid sequence. Indeed, the deletion of GRDD conferred a stable feature on topo IIα, whereas the fusion of GRDD rendered green fluorescent protein unstable under glucose starvation conditions. Nuclear localization was a prerequisite for GRDD function, because the inhibition of nuclear translocation resulted in the suppression of GRDD-mediated topo IIα degradation. Further, GRDD was identified as an interactive domain for Jab1/CSN5, which promoted the degradation of topo Iα in a manner dependent on the MPN (Mpr1p/ Prd1p N terminus) domain. Depleting Jab1/CSN5 by antisense oligonucleotide and treating cells with the CSN-associated kinase inhibitor, curcumin, inhibited topo IIα degradation induced by glucose starvation. These findings demonstrate that GRDD can act as a stress-activated degron for regulating topo IIα stability, possibly through interaction with the MPN domain of Jab1/CSN5.