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

The reactivation of the INK4-ARF locus, which is epigenetically repressed by Polycomb proteins in healthy cells, is a hallmark ofsenescence. One mechanism of reactivating Polycomb-silenced genes is mediated by the epigenetic factor ZRF1, which associateswith ubiquitinated histone H2A. We show that cells undergoing senescence following oncogenic Ras expression have increasedZRF1 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, ZRF1regulates the INK4-ARF locus during cellular proliferation and senescence, and alterations in ZRF1 may contribute to tumorigenesis.Oncogene (2013) 32, 2161–2168; doi:10.1038/onc.2012.241; published online 25 June 2012Keywords: chromatin; Polycomb; senescence; ZRF1INTRODUCTIONThe INK4-ARF locus, which encodes the three related genesp15INK4b, ARF and p16INK4a, has a key surveillance functionagainst tumorigenesis.