CDK inhibitor p21 is degraded by a proliferating cell nuclear antigen-coupled Cul4-DDB1Cdt2 pathway during s phase and after UV irradiation

Hideo Nishitani, Yasushi Shiomi, Hiroka Iida, Masato Michishita, Toshihiro Takami, Toshiki Tsurimoto

Research output: Contribution to journalArticle

187 Citations (Scopus)

Abstract

Previous reports showed that chromatin-associated PCNA couples DNA replication with Cul4-DDB1Cdt2-dependent proteolysis of the licensing factor Cdt1. The CDK inhibitor p21, another PCNA-binding protein, is also degraded both in S phase and after UV irradiation. Here we show that p21 is degraded by the same ubiquitin-proteasome pathway as Cdt1 in HeLa cells. When PCNA or components of Cul4-DDB1Cdt2 were silenced or when the PCNA binding site on p21 was mutated, degradation of p21 was prevented both in S phase and after UV irradiation. p21 was co- immunoprecipitated with Cul4A and DDB1 proteins when expressed in cells. The purified Cul4A-DDB1Cdt2 complex ubiquitinated p21 in vitro. Consistently, p21 protein levels are low during S phase and increase around G2 phase. Mutational analysis suggested that in addition to the PCNA binding domain, its flanking regions are also important for recognition by Cul4-DDB1Cdt2. Our findings provide a new aspect of proteolytic control of p21 during the cell cycle.

Original languageEnglish
Pages (from-to)29045-29052
Number of pages8
JournalJournal of Biological Chemistry
Volume283
Issue number43
DOIs
Publication statusPublished - Oct 24 2008

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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