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Molecular and Cellular Biology, June 2005, p. 5052-5060, Vol. 25, No. 12
0270-7306/05/$08.00+0     doi:10.1128/MCB.25.12.5052-5060.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

The HRPT2 Tumor Suppressor Gene Product Parafibromin Associates with Human PAF1 and RNA Polymerase II

Armelle Yart,1 Matthias Gstaiger,1 Christiane Wirbelauer,2 Maria Pecnik,1 Dimitrios Anastasiou,1 Daniel Hess,2 and Wilhelm Krek1*

Institute of Cell Biology, ETH Hönggerberg, CH-8093 Zurich, Switzerland,1 Friedrich Miescher Institute, Maulbeerstrasse 66, CH-4058 Basel, Switzerland2

Received 17 November 2004/ Returned for modification 21 December 2004/ Accepted 8 March 2005

Inactivation of the HRPT2 tumor suppressor gene is associated with the pathogenesis of the hereditary hyperparathyroidism-jaw tumor syndrome and malignancy in sporadic parathyroid tumors. The cellular function of the HPRT2 gene product, parafibromin, has not been defined yet. Here we show that parafibromin physically interacts with human orthologs of yeast Paf1 complex components, including PAF1, LEO1, and CTR9, that are involved in transcription elongation and 3' end processing. It also associates with modified forms of the large subunit of RNA polymerase II, in particular those phosphorylated on serine 5 or 2 within the carboxy-terminal domain, that are important for the coordinate recruitment of transcription elongation and RNA processing machineries during the transcription cycle. These interactions depend on a C-terminal domain of parafibromin, which is deleted in ca. 80% of clinically relevant mutations. Finally, RNAi-induced downregulation of parafibromin promotes entry into S phase, implying a role for parafibromin as an inhibitor of cell cycle progression. Taken together, these findings link the tumor suppressor parafibromin to the transcription elongation and RNA processing pathway as a PAF1 complex- and RNA polymerase II-bound protein. Dysfunction of this pathway may be a general phenomenon in the majority of cases of hereditary parathyroid cancer.

* Corresponding author. Mailing address: Institute of Cell Biology, ETH Hönggerberg, CH-8093 Zurich, Switzerland. Phone: 41-44-633-3447. Fax: 41-44-633-1357. E-mail: wilhelm.krek{at}cell.biol.ethz.ch.

Molecular and Cellular Biology, June 2005, p. 5052-5060, Vol. 25, No. 12
0022-538X/05/$08.00+0     doi:10.1128/MCB.25.12.5052-5060.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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