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 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.
Department of Differentiation and Cancer, Center for Genomic Regulation (CRG), and Universitat Pompeu Fabra (UPF), Barcelona, Spain.
J D
JD
Ribeiro
L
L
Morey
A
A
Mas
A
A
Gutierrez
N M
NM
Luis
S
S
Mejetta
H
H
Richly
S A
SA
Benitah
W M
WM
Keyes
L
L
Di Croce
D000818:Animals; D018797:Cell Cycle Proteins / Q000502:physiology; D002454:Cell Differentiation; D002460:Cell Line; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic; D016922:Cellular Senescence; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics* / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism / Q000502:physiology*; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D011905:Genes, ras; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D018832:Molecular Chaperones; D015513:Oncogene Proteins / Q000502:physiology*; D016601:RNA-Binding Proteins; D014212:Tretinoin / Q000494:pharmacology
D018797:Cell Cycle Proteins; D019941:Cyclin-Dependent Kinase Inhibitor p16; D004268:DNA-Binding Proteins; C414672:DNAJC2 protein, human; D018832:Molecular Chaperones; D015513:Oncogene Proteins; C116662:PRC1 protein, human; D016601:RNA-Binding Proteins; C096145:Zrf2 protein, mouse; D014212:Tretinoin