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

J. D. Ribeiro, L. Morey, A. Mas, A. Gutierrez, N. M. Luis, S. Mejetta, H. Richly, S. A. Benitah, W. M. Keyes, L. Di Croce

Research output: Contribution to journalArticle

17 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)2161-2168
Number of pages8
JournalOncogene
Volume32
Issue number17
DOIs
StatePublished - Jan 1 2013
Externally publishedYes

Keywords

  • Polycomb
  • ZRF1
  • chromatin
  • senescence

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

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    Ribeiro, J. D., Morey, L., Mas, A., Gutierrez, A., Luis, N. M., Mejetta, S., Richly, H., Benitah, S. A., Keyes, W. M., & Di Croce, L. (2013). ZRF1 controls oncogene-induced senescence through the INK4-ARF locus. Oncogene, 32(17), 2161-2168. https://doi.org/10.1038/onc.2012.241