The SUMO pathway is required for selective degradation of DNA topoisomerase IIbeta induced by a catalytic inhibitor ICRF-193(1).
DNA topoisomerase I and II have been shown to be modified with a ubiquitin-like protein SUMO in response to their specific inhibitors called 'poisons'. These drugs also damage DNA by stabilizing the enzyme-DNA cleavable complex and induce a degradation of the enzymes through the 26S proteasome system. A plausible link between sumoylation and degradation has not yet been elucidated. We demonstrate here that topoisomerase IIbeta, but not its isoform IIalpha, is selectively degraded through proteasome by exposure to the catalytic inhibitor ICRF-193 which does not damage DNA. The beta isoform immunoprecipitated from ICRF-treated cells was modified by multiple modifiers, SUMO-2/3, SUMO-1, and polyubiquitin. When the SUMO conjugating enzyme Ubc9 was conditionally knocked out, the ICRF-induced degradation of topoisomerase IIbeta did not occur, suggesting that the SUMO modification pathway is essential for the degradation.
Isik
Sevim
S
Department of Molecular Biology, Okayama University Graduate School of Medicine and Dentistry, Okayama 700-8558, Japan.
Sano
Kuniaki
K
Tsutsui
Kimiko
K
Seki
Masayuki
M
Enomoto
Takemi
T
Saitoh
Hisato
H
Tsutsui
Ken
K
D015153:Blotting, Western; D002384:Catalysis; D003546:Cysteine Endopeptidases / Q000378:metabolism*; D004250:DNA Topoisomerases, Type II / Q000096:biosynthesis / Q000378:metabolism*; D004268:DNA-Binding Proteins; D054659:Diketopiperazines; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006367:HeLa Cells; D006801:Humans; D006868:Hydrolysis; D009097:Multienzyme Complexes / Q000378:metabolism*; D010879:Piperazines / Q000494:pharmacology*; D046988:Proteasome Endopeptidase Complex; D025841:Small Ubiquitin-Related Modifier Proteins / Q000378:metabolism*; D059005:Topoisomerase II Inhibitors
D004268:DNA-Binding Proteins; D054659:Diketopiperazines; D004791:Enzyme Inhibitors; D009097:Multienzyme Complexes; D010879:Piperazines; D025841:Small Ubiquitin-Related Modifier Proteins; D059005:Topoisomerase II Inhibitors; C070899:4,4'-(1,2-dimethyl-1,2-ethanediyl)bis-2,6-piperazinedione; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex; D004250:DNA Topoisomerases, Type II