SUMO-1 conjugation to intact DNA topoisomerase I amplifies cleavable complex formation induced by camptothecin

Koji Horie, Akihiro Tomida, Yoshikazu Sugimoto, Toshiharu Yasugi, Hiroyuki Yoshikawa, Yuji Taketani, Takashi Tsuruo

研究成果: Article査読

51 被引用数 (Scopus)

抄録

DNA topoisomerase I (Topo1) manages the topological state of DNA. Cleavable complexes, the covalent Topo1-DNA intermediates, become DNA damaged when the catalytic cycles are inhibited by the anti-tumor drug camptothecin (CPT). Intriguingly, Topo1 is modified rapidly and extensively with SUMO-1, a ubiquitin-like protein, in response to CPT. This study shows that the sumoylation enhances the cleavable complex formation and apoptosis induced by CPT. Indeed, substitutions of Lys117 and Lys153, identified as Topo1 sumoylation sites, reduced the CPT-induced cleavable complexes without influencing its in vitro catalytic activity. Consistent with this observation, CPT-induced cleavable complexes of wild-type Topo1 increased in a sumoylation-dependent manner. We also found that Topo1 sumoylation occurred independently of CPT when Topo1 was inactivated by mutation of the catalytic Tyr723. These findings suggested that Topo1 inactivation by CPT treatment can trigger Topo1 sumoylation, leading to enhanced cleavable complex formation.

本文言語English
ページ(範囲)7913-7922
ページ数10
ジャーナルOncogene
21
52
DOI
出版ステータスPublished - 2002 11月 14
外部発表はい

ASJC Scopus subject areas

  • 分子生物学
  • 遺伝学
  • 癌研究

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