A novel zinc finger protein Zfp277 mediates transcriptional repression of the Ink4a/arf locus through polycomb repressive complex 1

• Published in: PloS one Vol. 5; no. 8; p. e12373
• Main Authors: Negishi, Masamitsu, Saraya, Atsunori, Mochizuki, Shinobu, Helin, Kristian, Koseki, Haruhiko, Iwama, Atsushi
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 24.08.2010; Public Library of Science (PLoS)
• Subjects: Aging; Animals; Antioxidants; Antioxidants - pharmacology; Binding; Cancer; Cell Line; Cellular Senescence - genetics; Cooperation; Cyclin-Dependent Kinase Inhibitor p16 - genetics; Cyclin-dependent kinase inhibitors; Dissociation; DNA binding proteins; Drosophila; Embryo fibroblasts; Embryos; Epigenetics; Fibroblasts; Fibroblasts - cytology; Fibroblasts - drug effects; Fibroblasts - metabolism; Gene expression; Gene Expression Regulation - drug effects; Gene regulation; Gene silencing; Genetic aspects; Genetic engineering; Genetic Loci - genetics; Genetics and Genomics/Epigenetics; Immunology; INK4 protein; INK4a protein; Insects; Kinases; Laboratories; Loci; Mammals; Medicine; Mice; Molecular Biology; Molecular Biology/Chromatin Structure; Molecular Biology/Histone Modification; Nuclear Proteins - metabolism; Oxidative Stress; Oxygen; p16 Protein; Polycomb group proteins; Polycomb Repressive Complex 1; Protein binding; Proteins; Proto-Oncogene Proteins - metabolism; Reactive oxygen species; Recruitment; Repressor Proteins - deficiency; Repressor Proteins - genetics; Repressor Proteins - metabolism; RNA polymerase; Senescence; Stem cells; Transcription (Genetics); Transcription factors; Transcription, Genetic; Tumor suppressor genes; Zinc; Zinc finger proteins; Zinc Fingers; Japan
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0012373

Polycomb group (PcG) proteins play a crucial role in cellular senescence as key transcriptional regulators of the Ink4a/Arf tumor suppressor gene locus. However, how PcG complexes target and contribute to stable gene silencing of the Ink4a/Arf locus remains little understood. We examined the function of Zinc finger domain-containing protein 277 (Zfp277), a novel zinc finger protein that interacts with the PcG protein Bmi1. Zfp277 binds to the Ink4a/Arf locus in a Bmi1-independent manner and interacts with polycomb repressor complex (PRC) 1 through direct interaction with Bmi1. Loss of Zfp277 in mouse embryonic fibroblasts (MEFs) caused dissociation of PcG proteins from the Ink4a/Arf locus, resulting in premature senescence associated with derepressed p16(Ink4a) and p19(Arf) expression. Levels of both Zfp277 and PcG proteins inversely correlated with those of reactive oxygen species (ROS) in senescing MEFs, but the treatment of Zfp277(-/-) MEFs with an antioxidant restored the binding of PRC2 but not PRC1 to the Ink4a/Arf locus. Notably, forced expression of Bmi1 in Zfp277(-/-) MEFs did not restore the binding of Bmi1 to the Ink4a/Arf locus and failed to bypass cellular senescence. A Zfp277 mutant that could not bind Bmi1 did not rescue Zfp277(-/-) MEFs from premature senescence. Our findings implicate Zfp277 in the transcriptional regulation of the Ink4a/Arf locus and suggest that the interaction of Zfp277 with Bmi1 is essential for the recruitment of PRC1 to the Ink4a/Arf locus. Our findings also highlight dynamic regulation of both Zfp277 and PcG proteins by the oxidative stress pathways.