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TFIIA transcriptional activity is controlled by a ‘cleave-and-run’ Exportin-1/Taspase 1-switch Free
Christian Schrenk 1,† , Verena Fetz 1,† , Cecilia Vallet 2 , Christina Heiselmayer 2 , Elisabeth Schro ¨der 2 , Astrid Hensel 2 , Angelina Hahlbrock 1 , De´sire´e Wu ¨nsch 1 , Dorothee Goesswein 1 , Carolin Bier 1 , Negusse Habtemichael 1 , Gu ¨nter Schneider 3 , Roland H. Stauber 1 , and Shirley K. Knauer 2, *
1 Molecular and Cellular Oncology/ENT, University Hospital of Mainz, 55101 Mainz, Germany
2 Molecular Biology, Centre for Medical Biotechnology (ZMB), University Duisburg-Essen, 45141 Essen, Germany
3 University Hospital Klinikum rechts der Isar, II. Medizinische Klinik, Technical University Mu ¨nchen, 81675 Munich, Germany
These authors contributed equally to this work *Correspondence to:Shirley K. Knauer, E-mail:
J Mol Cell Biol, Volume 10, Issue 1, February 2018, Pages 33-47
Keyword: cdnka2, cell cycle, Crm1, nuclear export, proteolysis, TBP

Transcription factor TFIIA is controlled by complex regulatory networks including proteolysis by the protease Taspase 1, though the full impact of cleavage remains elusive. Here, we demonstrate that in contrast to the general assumption, de novo produced TFIIA is rapidly confined to the cytoplasm via an evolutionary conserved nuclear export signal (NES, amino acids 21VINDVRDIFL30), interacting with the nuclear export receptor Exportin-1/chromosomal region maintenance 1 (Crm1). Chemical export inhibition or genetic inactivation of the NES not only promotes TFIIA’s nuclear localization but also affects its transcriptional activity. Notably, Taspase 1 processing promotes TFIIA’s nuclear accumulation by NES masking, and modulates its transcriptional activity. Moreover, TFIIA complex formation with the TATA box binding protein (TBP) is cooperatively enhanced by inhibition of proteolysis and nuclear export, leading to an increase of the cell cycle inhibitor p16INK, which is counteracted by prevention of TBP binding. We here identified a novel mechanism how proteolysis and nuclear transport cooperatively fine-tune transcriptional programs.