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Title DPY30 regulates pathways in cellular senescence through ID protein expression

Authors Elisabeth Simboeck, Arantxa Gutierrez, Luca Cozzuto, Malte Beringer, Livia Caizzi, William M. Keyes, Luciano Di Croce
Date 2013-08-14

Publisher The EMBO journal
DOI 10.1038/emboj.2013.159
Tag Blotting, Western, Cellular Senescence, Chromatin Immunoprecipitation, Colony-Forming Units Assay, Flow Cytometry, Fluorescent Antibody Technique, Gene Expression Regulation, Gene Knockdown Techniques, Humans, Inhibitor of Differentiation Protein 1, Microarray Analysis, Nuclear Proteins, RNA Interference, Reverse Transcriptase Polymerase Chain Reaction, Signal Transduction, beta-Galactosidase

Cellular senescence is an intrinsic defense mechanism to various cellular stresses: while still metabolically active, senescent cells stop dividing and enter a proliferation arrest. Here, we identify DPY30, a member of all mammalian histone H3K4 histone methyltransferases (HMTases), as a key regulator of the proliferation potential of human primary cells. Following depletion of DPY30, cells show a severe proliferation defect and display a senescent phenotype, including a flattened and enlarged morphology, elevated level of reactive oxygen species (ROS), increased SA-β-galactosidase activity, and formation of senescence-associated heterochromatin foci (SAHFs). While DPY30 depletion leads to a reduced level of H3K4me3-marked active chromatin, we observed a concomitant activation of CDK inhibitors, including p16INK4a, independent of H3K4me3. ChIP experiments show that key regulators of cell-cycle progression, including ID proteins, are under direct control of DPY30. Because ID proteins are negative regulators of the transcription factors ETS1/2, depletion of DPY30 leads to the transcriptional activation of p16INK4a by ETS1/2 and thus to a senescent-like phenotype. Ectoptic re-introduction of ID protein expression can partially rescue the senescence-like phenotype induced by DPY30 depletion. Thus, our data indicate that DPY30 controls proliferation by regulating ID proteins expression, which in turn lead to senescence bypass.

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