PML regulates PER2 nuclear localization and circadian function

EMBO J. 2012 Mar 21;31(6):1427-39. doi: 10.1038/emboj.2012.1. Epub 2012 Jan 24.


Studies have suggested that the clock regulator PER2 is a tumour suppressor. A cancer network involving PER2 raises the possibility that some tumour suppressors are directly involved in the mammalian clock. Here, we show that the tumour suppressor promyelocytic leukaemia (PML) protein is a circadian clock regulator and can physically interact with PER2. In the suprachiasmatic nucleus (SCN), PML expression and PML-PER2 interaction are under clock control. Loss of PML disrupts and dampens the expression of clock regulators Per2, Per1, Cry1, Bmal1 and Npas2. In the presence of PML and PER2, BMAL1/CLOCK-mediated transcription is enhanced. In Pml(-/-) SCN and mouse embryo fibroblast cells, the cellular distribution of PER2 is primarily perinuclear/cytoplasmic. PML is acetylated at K487 and its deacetylation by SIRT1 promotes PML control of PER2 nuclear localization. The circadian period of Pml(-/-) mice displays reduced precision and stability consistent with PML having a role in the mammalian clock mechanism.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Acetylation
  • Animals
  • CLOCK Proteins / genetics
  • CLOCK Proteins / metabolism
  • Cell Line
  • Cell Nucleus / genetics
  • Cell Nucleus / metabolism
  • Circadian Clocks / genetics*
  • Circadian Clocks / physiology
  • Circadian Rhythm / genetics*
  • Cytoplasm / metabolism
  • Fibroblasts / metabolism
  • Male
  • Mice
  • Nuclear Proteins / genetics*
  • Nuclear Proteins / metabolism*
  • Period Circadian Proteins / genetics*
  • Period Circadian Proteins / metabolism*
  • Promyelocytic Leukemia Protein
  • Sirtuin 1 / metabolism
  • Suprachiasmatic Nucleus / metabolism*
  • Transcription Factors / genetics*
  • Transcription Factors / metabolism*
  • Transcription, Genetic / genetics
  • Tumor Suppressor Proteins / genetics*
  • Tumor Suppressor Proteins / metabolism*


  • Nuclear Proteins
  • Per2 protein, mouse
  • Period Circadian Proteins
  • Pml protein, mouse
  • Promyelocytic Leukemia Protein
  • Transcription Factors
  • Tumor Suppressor Proteins
  • CLOCK Proteins
  • Sirt1 protein, mouse
  • Sirtuin 1