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BRCA1 cooperates with NUFIP and P-TEFb to activate transcription by RNA polymerase II

Oncogene volume 23, pages 5316–5329 (2004)Cite this article

Abstract

The tumor suppressor gene product BRCA1 is a component of the RNA polymerase II (pol II) holoenzyme that is involved, through binding to various regulatory proteins, in either activation or repression of transcription. Using a yeast two-hybrid screen, we have identified a human zinc-finger-containing protein NUFIP that interacts with BRCA1. The ubiquitous, stably expressed, nuclear protein NUFIP specifically stimulates activator-independent pol II transcription in vitro and in vivo. Immunodepletion of the endogenous NUFIP causes a marked decrease of pol II transcription, which is then shown to be restored by stable complex of ectopically produced NUFIP and associated factors. NUFIP not only interacts with BRCA1 but also associates with the positive elongation factor P-TEFb through interaction with the regulatory Cyclin T1 subunit. Cyclin T1 is required for BRCA1- and NUFIP-dependent synergistic activation of pol II transcription in 293 cells. Mutation of the zinc-finger domain abolishes the NUFIP-mediated transcriptional activation. We show that NUFIP is associated with preinitiation complexes, open transcription complexes, and elongation complexes. In addition, NUFIP facilitates ATP-dependent dissociation of hyperphosphorylated pol II from open transcription complexes in vitro.

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Acknowledgements

We thank Wen-Hwa Lee in whose laboratory some of these experiments were carried out. We thank Phang-Lang Chen, Yumay Chen, and Thomas Boyer for valuable reagents and advice. We also thank Alexandre Akoulitchev for useful discussions. We thank David Price for the pcDNA3-Cyclin T1 expression vector. The constructs encoding GST-tagged Cyclin T1 and Cyclin K were kindly provided by Matija Peterlin and Stephen Elledge.

This work was supported in part by MRC Senior Fellowship G117/309 (to SM), NIH grants (to W-HL), and VA Career Developmental Award (to HKC).

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  1. Sir William Dunn School of Pathology, University of Oxford, South Parks Road, Oxford, OX1 3RE, UK

    Pavel Čabart & Shona Murphy

  2. Division of Hematology/Oncology, UC Davis Cancer Center, 4501 X Street, Sacramento, 95817, CA, USA

    Helen K Chew

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Correspondence to Pavel Čabart.

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Čabart, P., Chew, H. & Murphy, S. BRCA1 cooperates with NUFIP and P-TEFb to activate transcription by RNA polymerase II. Oncogene 23, 5316–5329 (2004). https://doi.org/10.1038/sj.onc.1207684

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