학술논문
The PRC2.1 Subcomplex Opposes G1 Progression through Regulation of CCND1 and CCND2.
Document Type
Author
Longhurst AD; University of California, San Francisco, San Francisco, CA 94158, USA.; Tetrad Graduate Program, University of California, San Francisco, San Francisco, CA 94158, USA.; Wang K; Department of Molecular Genetics, University of Toronto, 160 College Street, Toronto, Ontario M5S 3E1, Canada.; The Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, ON, Canada.; Suresh HG; Department of Molecular Genetics, University of Toronto, 160 College Street, Toronto, Ontario M5S 3E1, Canada.; Ketavarapu M; Gladstone Institute for Data Science and Biotechnology, J. David Gladstone Institutes, San Francisco, CA, USA.; Department of Biochemistry and Biophysics, University of California San Francisco, San Francisco, CA, USA.; Ward HN; Bioinformatics and Computational Biology Graduate Program, University of Minnesota - Twin Cities Minneapolis MN USA.; Jones IR; Institute for Human Genetics, University of California, San Francisco, San Francisco, CA, USA.; Pharmaceutical Sciences and Pharmacogenomics Graduate Program, University of California.; Narayan V; Institute for Human Genetics, University of California, San Francisco, San Francisco, CA, USA.; Hundley FV; University of California, San Francisco, San Francisco, CA 94158, USA.; Tetrad Graduate Program, University of California, San Francisco, San Francisco, CA 94158, USA.; Department of Cell Biology, Blavatnik Institute of Harvard Medical School, Boston, MA 02115, USA.; Hassan AZ; Department of Computer Science and Engineering, University of Minnesota - Twin Cities Minneapolis MN USA.; Boone C; Department of Molecular Genetics, University of Toronto, 160 College Street, Toronto, Ontario M5S 3E1, Canada.; The Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, ON, Canada.; Myers CL; Bioinformatics and Computational Biology Graduate Program, University of Minnesota - Twin Cities Minneapolis MN USA.; Department of Cell Biology, Blavatnik Institute of Harvard Medical School, Boston, MA 02115, USA.; Shen Y; Institute for Human Genetics, University of California, San Francisco, San Francisco, CA, USA.; Department of Neurology, University of California, San Francisco, San Francisco, CA, USA.; Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA, USA.; Ramani V; Gladstone Institute for Data Science and Biotechnology, J. David Gladstone Institutes, San Francisco, CA, USA.; Department of Biochemistry and Biophysics, University of California San Francisco, San Francisco, CA, USA.; Andrews BJ; The Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, ON, Canada.; Toczyski DP; University of California, San Francisco, San Francisco, CA 94158, USA.; Department of Biochemistry and Biophysics, University of California San Francisco, San Francisco, CA, USA.; Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA, USA.
Source
Country of Publication: United States NLM ID: 101680187 Publication Model: Electronic Cited Medium: Internet NLM ISO Abbreviation: bioRxiv Subsets: PubMed not MEDLINE
Subject
Language
English
Abstract
Progression through the G1 phase of the cell cycle is the most highly regulated step in cellular division. We employed a chemogenomics approach to discover novel cellular networks that regulate cell cycle progression. This approach uncovered functional clusters of genes that altered sensitivity of cells to inhibitors of the G1/S transition. Mutation of components of the Polycomb Repressor Complex 2 rescued growth inhibition caused by the CDK4/6 inhibitor palbociclib, but not to inhibitors of S phase or mitosis. In addition to its core catalytic subunits, mutation of the PRC2.1 accessory protein MTF2, but not the PRC2.2 protein JARID2, rendered cells resistant to palbociclib treatment. We found that PRC2.1 (MTF2), but not PRC2.2 (JARID2), was critical for promoting H3K27me3 deposition at CpG islands genome-wide and in promoters. This included the CpG islands in the promoter of the CDK4/6 cyclins CCND1 and CCND2, and loss of MTF2 lead to upregulation of both CCND1 and CCND2. Our results demonstrate a role for PRC2.1, but not PRC2.2, in promoting G1 progression.