The ARF Tumor Suppressor Controls Ribosome Biogenesis by Regulating the RNA Polymerase I Transcription Factor TTF-I

SummaryThe p14/p19ARF (ARF) product of the CDKN2A gene displays tumor suppressor activity both in the presence and absence of p53/TP53. In p53-negative cells, ARF arrests cell proliferation, at least in part, by suppressing ribosomal RNA synthesis. We show that ARF does this by controlling the subnuclear localization of the RNA polymerase I transcription termination factor, TTF-I. TTF-I shuttles between nucleoplasm and nucleolus with the aid of the chaperone NPM/B23 and a nucleolar localization sequence within its N-terminal regulatory domain. ARF inhibits nucleolar import of TTF-I by binding to this nucleolar localization sequence, causing the accumulation of TTF-I in the nucleoplasm. Depletion of TTF-I recapitulates the effects of ARF on ribosomal RNA synthesis and is rescued by the introduction of a TTF-I transgene. Thus, our data delineate the pathway by which ARF regulates ribosomal RNA synthesis and provide a compelling explanation for the role of NPM.

Graphical AbstractFigure optionsDownload high-quality image (169 K)Download as PowerPoint slideHighlights▸ ARF tumor suppressor targets TTF-I to repress ribosome biogenesis ▸ TTF-I is essential for ribosomal RNA synthesis in the nucleolus ▸ Nucleolar localization of TTF-I requires the chaperone NPM/B23 ▸ ARF binds and inactivates the nucleolar localization motif of TTF-I