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

J Biol Chem. 2011 Sep 2;286(35):30462-70. doi: 10.1074/jbc.M111.273508. Epub 2011 Jul 8.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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 / chemistry
  • Ubiquitin-Protein Ligases / chemistry*

Substances

  • Chromatin
  • Cullin 1
  • Cullin Proteins
  • F-Box Proteins
  • S-Phase Kinase-Associated Proteins
  • Ubiquitin
  • Histone Demethylases
  • Jumonji Domain-Containing Histone Demethylases
  • KDM4A protein, human
  • Ubiquitin-Protein Ligases
  • Proteasome Endopeptidase Complex
  • FbxL4 protein, human