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Uncleaved TFIIA Is a Substrate for Taspase 1 and Active in Transcription

Huiqing Zhou,¹ Salvatore Spicuglia,^1, James J.-D. Hsieh,^2, Dimitra J. Mitsiou,³ Torill Høiby,¹ Gert Jan C. Veenstra,¹ Stanley J. Korsmeyer,² and Hendrik G. Stunnenberg^1*

NCMLS, Department of Molecular Biology, 191, Radboud University of Nijmegen, 6500 HB Nijmegen, The Netherlands,¹ Howard Hughes Medical Institute, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115,² Molecular Endocrinology Program, Institute of Biological Research and Biotechnology, The National Hellenic Research Foundation, 11635 Athens, Greece³

Received 3 January 2006/ Accepted 3 January 2006

In higher eukaryotes, the large subunit of the general transcription factor TFIIA is encoded by the single TFIIAß gene and posttranslationally cleaved into and ß subunits. The molecular mechanisms and biological significance of this proteolytic process have remained obscure. Here, we show that TFIIA is a substrate of taspase 1 as reported for the trithorax group mixed-lineage leukemia protein. We demonstrate that recombinant taspase 1 cleaves TFIIA in vitro. Transfected taspase 1 enhances cleavage of TFIIA, and RNA interference knockdown of endogenous taspase 1 diminishes cleavage of TFIIA in vivo. In taspase 1^–/– MEF cells, only uncleaved TFIIA is detected. In Xenopus laevis embryos, knockdown of TFIIA results in phenotype and expression defects. Both defects can be rescued by expression of an uncleavable TFIIA mutant. Our study shows that uncleaved TFIIA is transcriptionally active and that cleavage of TFIIA does not serve to render TFIIA competent for transcription. We propose that cleavage fine tunes the transcription regulation of a subset of genes during differentiation and development.

Present address: Centre d'Immunologie de Marseille-Luminy, Parc Scientifique et Technologique de Luminy, 13009 Marseille, France.

Present address: Department of Medicine, Molecular Oncology, Siteman Cancer Center, Washington University, St. Louis, Mo.

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