The SKP1-Cul1-F-box and leucine-rich repeat protein 4 (SCF-FbxL4) ubiquitin ligase regulates lysine demethylase 4A (KDM4A)/Jumonji domain-containing 2A (JMJD2A) protein

Capucine Van Rechem, Joshua C. Black, Tarek Abbas, Andrew Allen, Claire A. Rinehart, Guo Cheng Yuan, Anindya Dutta, Johnathan R. Whetstine

Research output: Contribution to journalArticlepeer-review

55 Scopus citations

Abstract

Chromatin-modifying enzymes play a fundamental role in regulating chromatin structure so that DNA replication is spatially and temporally coordinated. For example, the lysine demethylase 4A/Jumonji domain-containing 2A (KDM4A/JMJD2A) is tightly regulated during the cell cycle. Overexpression of JMJD2A leads to altered replication timing and faster S phase progression. In this study, we demonstrate that degradation of JMJD2A is regulated by the proteasome. JMJD2A turnover is coordinated through the SKP1-Cul1-F-box ubiquitin ligase complex that contains cullin 1 and the F-box and leucine-rich repeat protein 4 (FbxL4). This complex interacted with JMJD2A. Ubiquitin overexpression restored turnover and blocked the JMJD2A-dependent faster S phase progression in a cullin 1-dependent manner. Furthermore, increased ubiquitin levels decreased JMJD2A occupancy and BrdU incorporation at target sites. This study highlights a finely tuned mechanism for regulating histone demethylase levels and emphasizes the need to tightly regulate chromatin modifiers so that the cell cycle occurs properly.

Original languageEnglish
Pages (from-to)30462-30470
Number of pages9
JournalJournal of Biological Chemistry
Volume286
Issue number35
DOIs
StatePublished - Sep 2 2011
Externally publishedYes

Keywords

  • Base Sequence
  • Binding Sites
  • Cell Cycle
  • Chromatin/chemistry
  • Cullin Proteins/chemistry
  • DNA Replication
  • F-Box Proteins/chemistry
  • Histone Demethylases/chemistry
  • Humans
  • Jumonji Domain-Containing Histone Demethylases/chemistry
  • Proteasome Endopeptidase Complex/chemistry
  • Protein Binding
  • Protein Structure, Tertiary
  • S-Phase Kinase-Associated Proteins/chemistry
  • Ubiquitin-Protein Ligases/chemistry
  • Ubiquitin/chemistry

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