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Molecular and Cellular Biology, April 1999, p. 2644-2649, Vol. 19, No. 4
0270-7306/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.

Inhibition of Nuclear Receptor Signalling by Poly(ADP-Ribose) Polymerase

Takahide Miyamoto,* Tomoko Kakizawa, and Kiyoshi Hashizume

Department of Geriatrics, Endocrinology and Metabolism, Shinshu University School of Medicine, Matsumoto 390-8621, Japan

Received 19 November 1998/Returned for modification 4 January 1999/Accepted 12 January 1999

Mammalian poly(ADP-ribose) polymerase (PARP) is a nuclear chromatin-associated protein with a molecular mass of 114 kDa that catalyzes the transfer of ADP-ribose units from NAD+ to nuclear proteins that are located within chromatin. We report here the identification of a novel property of PARP as a modulator of nuclear receptor signalling. PARP bound directly to retinoid X receptors (RXR) and repressed ligand-dependent transcriptional activities mediated by heterodimers of RXR and thyroid hormone receptor (TR). The interacting surface is located in the DNA binding domain of RXRalpha . Gel shift assays demonstrated that PARP bound to TR-RXR heterodimers on the response element. Overexpression of wild-type PARP selectively blocked nuclear receptor function in transient transfection experiments, while enzyme-defective mutant PARP did not show significant inhibition, suggesting that the essential role of poly(ADP-ribosyl) enzymatic activity is in gene regulation by nuclear receptors. Furthermore, PARP fused to the Gal4 DNA binding domain suppressed the transcriptional activity of the promoter harboring the Gal4 binding site. Thus, PARP has transcriptional repressor activity when recruited to the promoter. These results indicates that poly(ADP-ribosyl)ation is a negative cofactor in gene transcription, regulating a member of the nuclear receptor superfamily.

* Corresponding author. Mailing address: Department of Geriatrics, Endocrinology and Metabolism, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto 390-8621, Japan. Phone: 81-263-37-2686. Fax: 81-263-37-2710. E-mail: miyamoto{at}hsp.md.shinshu-u.ac.jp.

Molecular and Cellular Biology, April 1999, p. 2644-2649, Vol. 19, No. 4
0270-7306/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.


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