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Molecular and Cellular Biology, December 2004, p. 10593-10610, Vol. 24, No. 24
0270-7306/04/$08.00+0     DOI: 10.1128/MCB.24.24.10593-10610.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

PIAS-1 Is a Checkpoint Regulator Which Affects Exit from G₁ and G₂ by Sumoylation of p73

Biochemistry Laboratory, IDI-IRCCS, c/o Department of Experimental Medicine and Biochemical Sciences, University of Rome "Tor Vergata," Rome, Italy,³ Toxicology Unit, Medical Research Council, Leicester University, Leicester,¹ Medical Molecular Biology Unit, Institute of Child Health, University College London,² Department of Cystic Fibrosis, National Heart and Lung Institute, London, United Kingdom,⁵ Molecular Cell Biology Laboratory, Department of Genetics, The Smurfit Institute, Trinity College, Dublin, Ireland⁴

Received 26 March 2004/ Returned for modification 14 May 2004/ Accepted 23 September 2004

p73 is a recently described member of the p53 family, and, like p53, it undergoes a number of posttranslational modifications. Here we show, by yeast two-hybrid screening, pull-down assays, and coimmunoprecipitation, that p73, -ß, and - bind to the protein inhibitor of activated STAT-1 (PIAS-1) and that this binding stabilizes p73. PIAS-1 also sumoylates p73, although not the C-terminally truncated isoforms p73ß and -, and this requires the RING finger domain of PIAS-1. The Np73 isoform can also bind, and be sumoylated by, PIAS-1. PIAS-1-mediated sumoylation decreases p73 transcriptional activity on several target promoters, such as Bax. p73 is colocalized in the nucleus with PIAS-1, and sumoylated p73 is located exclusively in the nuclear matrix. PIAS-1 is expressed predominantly during S phase, and PIAS-1 overexpression reduces p73-mediated transcription of p21, with a reduction of cells in G₁ and cell cycle reentry. Inhibition of endogenous PIAS-1 by RNA interference reduces the proportion of cells in S phase and induces G₂ arrest. These data suggest that PIAS-1, acting partly through binding and sumoylation of p73, is an important component of the cell cycle machinery.

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