ZRF1 controls oncogene-induced senescence through the INK4-ARF locus

Oncogene. 2013 Apr 25;32(17):2161-8. doi: 10.1038/onc.2012.241. Epub 2012 Jun 25.


The reactivation of the INK4-ARF locus, which is epigenetically repressed by Polycomb proteins in healthy cells, is a hallmark of senescence. One mechanism of reactivating Polycomb-silenced genes is mediated by the epigenetic factor ZRF1, which associates with ubiquitinated histone H2A. We show that cells undergoing senescence following oncogenic Ras expression have increased ZRF1 levels, and that this binds to the p15INK4b, ARF and p16INK4a promoters. Furthermore, ZRF1 depletion in oncogenic Ras-expressing cells restores proliferation by preventing Arf and p16Ink4a expression, consequently bypassing senescence. Thus, ZRF1 regulates the INK4-ARF locus during cellular proliferation and senescence, and alterations in ZRF1 may contribute to tumorigenesis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Cycle Proteins / physiology
  • Cell Differentiation
  • Cell Line
  • Cell Proliferation
  • Cell Transformation, Neoplastic
  • Cellular Senescence*
  • Cyclin-Dependent Kinase Inhibitor p16 / genetics*
  • Cyclin-Dependent Kinase Inhibitor p16 / metabolism
  • DNA-Binding Proteins / metabolism
  • DNA-Binding Proteins / physiology*
  • Gene Expression Regulation, Neoplastic
  • Gene Silencing
  • Genes, ras*
  • Humans
  • Mice
  • Mice, Inbred C57BL
  • Molecular Chaperones
  • Oncogene Proteins / physiology*
  • RNA-Binding Proteins
  • Tretinoin / pharmacology


  • Cell Cycle Proteins
  • Cyclin-Dependent Kinase Inhibitor p16
  • DNA-Binding Proteins
  • DNAJC2 protein, human
  • Molecular Chaperones
  • Oncogene Proteins
  • PRC1 protein, human
  • RNA-Binding Proteins
  • Zrf2 protein, mouse
  • Tretinoin