ATM kinase enables the functional axis of YAP, PML and p53 to ameliorate loss of Werner protein-mediated oncogenic senescence

• Published in: Cell death and differentiation Vol. 20; no. 11; pp. 1498 - 1509
• Main Authors: Fausti, F, Di Agostino, S, Cioce, M, Bielli, P, Sette, C, Pandolfi, P P, Oren, M, Sudol, M, Strano, S, Blandino, G
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01-11-2013; Nature Publishing Group
• Subjects: 631/80/509; 692/420/755; 692/699/317; Apoptosis; Ataxia Telangiectasia Mutated Proteins - metabolism; Biochemistry; Biomedical and Life Sciences; Cancer; Cell Biology; Cell Cycle Analysis; Cell death; Cell growth; Cellular Senescence - physiology; Exodeoxyribonucleases - deficiency; Exodeoxyribonucleases - metabolism; Genotype & phenotype; HCT116 Cells; HEK293 Cells; Humans; Kinases; Life Sciences; MCF-7 Cells; Medicine; Nuclear Proteins - metabolism; Original Paper; p38 Mitogen-Activated Protein Kinases - metabolism; Phosphorylation; Promyelocytic Leukemia Protein; Proteins; RecQ Helicases - deficiency; RecQ Helicases - metabolism; Senescence; Signal Transduction; Stem Cells; Transcription Factors - metabolism; Transfection; Tumor Suppressor Protein p53 - metabolism; Tumor Suppressor Proteins - metabolism; Werner Syndrome Helicase; Italy; Israel; United States > US; Rome Italy; cellular senescence; Yes-associated protein (YAP); Werner syndrome; ATM kinase
• ISSN: 1350-9047; 1476-5403
• DOI: 10.1038/cdd.2013.101

Werner syndrome (WS) results from dysfunction of the WRN protein, and is associated with premature aging and early death. Here we report that loss of WRN function elicits accumulation of the Yes-associated protein (YAP protein), a major effector of the Hippo tumor suppressor pathway, both experimentally and in WS-derived fibroblasts. YAP upregulation correlates with slower cell proliferation and accelerated senescence, which are partially mediated by the formation of a complex between YAP and the PML protein, whose activity promotes p53 activation. The ATM kinase is necessary for YAP and PML accumulation in WRN-depleted cells. Notably, the depletion of either YAP or PML partially impairs the induction of senescence following WRN loss. Altogether, our findings reveal that loss of WRN activity triggers the activation of an ATM-YAP-PML-p53 axis, thereby accelerating cellular senescence. The latter has features of SASP (senescence-associated secretory phenotype), whose protumorigenic properties are potentiated by YAP, PML and p53 depletion.