Interaction between glucose-regulated destruction domain of DNA topoisomerase IIalpha and MPN domain of Jab1/CSN5.
DNA topoisomerase (topo) IIalpha, 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 IIalpha 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 IIalpha, 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 IIalpha degradation. Further, GRDD was identified as an interactive domain for Jab1/CSN5, which promoted the degradation of topo IIalpha 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 IIalpha degradation induced by glucose starvation. These findings demonstrate that GRDD can act as a stress-activated degron for regulating topo IIalpha stability, possibly through interaction with the MPN domain of Jab1/CSN5.
Yun
Jisoo
J
Institute of Molecular and Cellular Biosciences, The University of Tokyo, 1-1-1,Yayoi, Bunkyo-ku, Tokyo 113-0032, Japan.
Tomida
Akihiro
A
Andoh
Toshiwo
T
Tsuruo
Takashi
T
D000251:Adenosine Triphosphatases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D000951:Antigens, Neoplasm; D001483:Base Sequence; D000075686:COP9 Signalosome Complex; D045744:Cell Line, Tumor; D004250:DNA Topoisomerases, Type II / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D005947:Glucose / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D047908:Intracellular Signaling Peptides and Proteins; D016296:Mutagenesis; D019913:Nuclear Localization Signals; D020319:Oligodeoxyribonucleotides, Antisense / Q000235:genetics; D010447:Peptide Hydrolases; D017434:Protein Structure, Tertiary; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D014162:Transfection
D000951:Antigens, Neoplasm; D004268:DNA-Binding Proteins; D047908:Intracellular Signaling Peptides and Proteins; D019913:Nuclear Localization Signals; D020319:Oligodeoxyribonucleotides, Antisense; D011993:Recombinant Fusion Proteins; D014157:Transcription Factors; D010447:Peptide Hydrolases; C501488:COPS5 protein, human; D000075686:COP9 Signalosome Complex; D000251:Adenosine Triphosphatases; D004250:DNA Topoisomerases, Type II; D005947:Glucose