Loss of CCDC6, the First Identified RET Partner Gene, Affects pH2AX S139 Levels and Accelerates Mitotic Entry upon DNA Damage(361 views) Merolla F, Luise C, Muller MT, Pacelli R, Fusco A, Celetti A
Plosone (ISSN: 1932-6203, 1932-6203electronic, 1932-6203linking), 2012 May 24; 7(5): N/D-N/D.
Keywords: Histone H2ax, Phosphatase, Phosphoprotein Phosphatase, Phosphoprotein Phosphatase 4c, Protein Ph2ax, Unclassified Drug, Ccdc6 Protein, Human, Cytoskeleton Protein, H2afx Protein, Article, Carcinogenesis, Catalysis, Ccdc6 Gene, Cell Cycle Arrest, Cell Cycle G2 Phase, Cell Loss, Cell Maturation, Cell Transport, Controlled Study, Dna Damage, Dna Repair, Enzyme Activation, Enzyme Activity, Gene Function, Gene Fusion, Gene Inactivation, Gene Interaction, Gene Loss, Genetic Conservation, Genomic Instability, Genotoxicity, High Throughput Screening, Human Cell, Mitosis, Protein Analysis, Protein Dephosphorylation, Protein Interaction, Cell Line, Gene Silencing, Hela Cell, Metabolism, Neoplasm, Cytoskeletal Proteins,
Affiliations: *** IBB - CNR ***
Istituto di Endocrinologia ed Oncologia Sperimentale, CNR, Naples, Italy
Dipartimento di Biologia e Patologia Cellulare e Molecolare, Università Federico II, Naples, Italy
Department of Molecular Biology and Microbiology, College of Medicine, University of Central Florida, Orlando, FL, United States
Dipartimento di Scienze Biomorfologiche e Funzionali, Università Federico II, Naples, Italy
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Mac rek, L., Lindqvist, A., Voets, O., Kool, J., Vos, H. R., Wip1 phosphatase is associated with chromatin and dephosphorylates gammaH2AX to promote checkpoint inhibition (2010) Oncogene, 29, pp. 2281-2291
Freeman, A. K., Monteiro, A. N., Phosphatases in the cellular response to DNA damage (2010) Cell Commun Signal, 8, p. 27
Halazonetis, T. D., Gorgoulis, V. G., Bartek, J., An oncogene-induced DNA damage model for cancer development (2008) Science, 319, pp. 1352-1355
Pear, W. S., Nolan, G. P., Scott, M. L., Baltimore, D., Production of high-titer helper-free retroviruses by transient transfection (1993) Proc Natl Acad Sci U S A, 90, pp. 8392-8396
Scherer, W. F., Syverton, J. T., Gey, G. O., Studies on the propagation in vitro of poliomyelitis viruses. IV. Viral multiplication in a stable strain of human malignant epithelial cells (strain HeLa) derived from an epidermoid carcinoma of the cervix (1953) J Exp Med, 97, pp. 695-710
Loss of CCDC6, the First Identified RET Partner Gene, Affects pH2AX S139 Levels and Accelerates Mitotic Entry upon DNA Damage
CCDC6 was originally identified in chimeric genes caused by chromosomal translocation involving the RET proto-oncogene in some thryoid tumors mostly upon ionizing radiation exposure. Recognised as a pro-apoptotic phosphoprotein that negatively regulates CREB1-dependent transcription, CCDC6 is an ATM substrate that is responsive to genotoxic stress. Here we report that following genotoxic stress, loss or inactivation of CCDC6 in cancers that carry the CCDC6 fusion, accelerates the dephosphorylation of pH2AX S139, resulting in defective G2 arrest and premature mitotic entry. Moreover, we show that CCDC6 depleted cells appear to repair DNA damaged in a shorter time compared to controls, based on reporter assays in cells. High-troughput proteomic screening predicted the interaction between the CCDC6 gene product and the catalytic subunit of Serin-Threonin Protein Phosphatase 4 (PP4c) recently identified as the evolutionarily conserved pH2AX S139 phosphatase that is activated upon DNA Damage. We describe the interaction between CCDC6 and PP4c and we report the modulation of PP4c enzymatic activity in CCDC6 depleted cells. We discuss the functional significance of CCDC6-PP4c interactions and hypothesize that CCDC6 may act in the DNA Damage Response by negatively modulating PP4c activity. Overall, our data suggest that in primary tumours the loss of CCDC6 function could influence genome stability and thereby contribute to carcinogenesis.
Loss of CCDC6, the First Identified RET Partner Gene, Affects pH2AX S139 Levels and Accelerates Mitotic Entry upon DNA Damage