Circadian regulator CLOCK is a histone acetyltransferase

Cell. 2006 May 5;125(3):497-508. doi: 10.1016/j.cell.2006.03.033.

Abstract

The molecular machinery that governs circadian rhythmicity comprises proteins whose interplay generates time-specific transcription of clock genes. The role of chromatin remodeling in a physiological setting such as the circadian clock is yet unclear. We show that the protein CLOCK, a central component of the circadian pacemaker, has histone acetyltransferase (HAT) activity. CLOCK shares homology with acetyl-coenzyme A binding motifs within the MYST family of HATs. CLOCK displays high sequence similarity to ACTR, a member of SRC family of HATs, with which it shares also enzymatic specificity for histones H3 and H4. BMAL1, the heterodimerization partner of CLOCK, enhances HAT function. The HAT activity of CLOCK is essential to rescue circadian rhythmicity and activation of clock genes in Clock mutant cells. Identification of CLOCK as a novel type of DNA binding HAT reveals that chromatin remodeling is crucial for the core clock mechanism and identifies unforeseen links between histone acetylation and cellular physiology.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ARNTL Transcription Factors
  • Acetylation
  • Acetyltransferases / classification
  • Acetyltransferases / genetics
  • Acetyltransferases / metabolism
  • Amino Acid Motifs / physiology
  • Animals
  • Basic Helix-Loop-Helix Transcription Factors / genetics
  • Basic Helix-Loop-Helix Transcription Factors / metabolism
  • Binding Sites / physiology
  • CLOCK Proteins
  • Cell Line
  • Cell Line, Tumor
  • Chromatin Assembly and Disassembly / genetics*
  • Circadian Rhythm / genetics*
  • Histone Acetyltransferases / genetics
  • Histone Acetyltransferases / metabolism*
  • Histones / metabolism*
  • Humans
  • Mice
  • Mice, Mutant Strains
  • Mice, Transgenic
  • Nuclear Receptor Coactivator 1
  • Nuclear Receptor Coactivator 3
  • Oncogene Proteins / classification
  • Oncogene Proteins / genetics
  • Oncogene Proteins / metabolism
  • Sequence Homology, Amino Acid
  • Trans-Activators / classification*
  • Trans-Activators / genetics
  • Trans-Activators / metabolism*
  • Transcription Factors / classification
  • Transcription Factors / genetics
  • Transcription Factors / metabolism

Substances

  • ARNTL Transcription Factors
  • ARNTL protein, human
  • Arntl protein, mouse
  • Basic Helix-Loop-Helix Transcription Factors
  • Histones
  • Oncogene Proteins
  • Trans-Activators
  • Transcription Factors
  • Acetyltransferases
  • CLOCK Proteins
  • CLOCK protein, human
  • Clock protein, mouse
  • Histone Acetyltransferases
  • NCOA1 protein, human
  • NCOA3 protein, human
  • Ncoa1 protein, mouse
  • Ncoa3 protein, mouse
  • Nuclear Receptor Coactivator 1
  • Nuclear Receptor Coactivator 3