Pf1, also known as Phf12 (plant homeodomain [PHD] zinc finger protein 12), is a member of the PHD zinc finger family of proteins. Pf1 associates with a chromatin-interacting protein complex comprised of MRG15, Sin3B, and histone deacetylase 1 (HDAC1) that functions as a transcriptional modulator. The biological function of Pf1 remains largely elusive. We undertook the generation of Pf1 knockout mice to elucidate its physiological role. We demonstrate that Pf1 is required for mid-to late gestation viability. Pf1 inactivation impairs the proliferative potential of mouse embryonic fibroblasts (MEFs) and is associated with a significant decrease in bromodeoxyuridine incorporation; an increase in senescence-associated ␤-galactosidase (SA-␤-Gal) activity, a marker of cellular senescence; and elevated levels of phosphorylated H2AX (␥-H2A.X), a marker associated with DNA double-strand breaks. Analysis of transcripts differentially expressed in wild-type and Pf1-deficient cells revealed the impact of Pf1 in multiple regulatory arms of the ribosome biogenesis pathways. Strikingly, assessment of the morphology of the nucleoli exposed an abnormal nucleolar structure in Pf1-deficient cells. Finally, proteomic analysis of the Pf1-interacting complexes highlighted proteins involved in ribosome biogenesis. Taken together, our data reveal an unsuspected function for the Pf1-associated chromatin complex in the ribosomal biogenesis and senescence pathways.KEYWORDS transcription, ribosome, Pf1, senescence, nucleolus P f1, also known as Phf12 (plant homeodomain [PHD] zinc finger protein 12), is a member of the PHD zinc finger family of proteins. PHD domains are small, 50-to 80-amino-acid-long domains often found in clusters of two or three and/or in the proximity of other chromatin-interacting domains, such as bromo-or chromodomains. Consistently, many of the PHD-containing proteins are nuclear proteins that interact with chromatin. Increasing evidence suggests that PHD domains are capable of recognizing modified and unmodified histone tails and that PHD domain-containing proteins act as epigenetic readers (1).The Pf1 gene is conserved throughout evolution, and the Pf1 protein, like its Saccharomyces cerevisiae yeast homolog, Rco1, contains two PHD domains in its N terminus. Mammalian Pf1 was first identified in a yeast two-hybrid screen for proteins interacting with the paired amphipathic helix 2 (PAH2) domain of Sin3A and shown to function as a transcriptional repressor (2). A later report identified Pf1 to be one of the components of the human MRG15 complex, together with Sin3B but not together with its close homolog, Sin3A (3). The PHD domains of Pf1 are important for the interaction with the MRG domain of MRG15, which relies mainly on hydrophobic interactions (3-5). The interaction of Pf1 with a complex containing Sin3B but not Sin3A was also confirmed in experiments identifying associations between Sin3B, histone deacetylase