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Molecular and Cellular Biology, March 2004, p. 2526-2535, Vol. 24, No. 6
0270-7306/04/$08.00+0     DOI: 10.1128/MCB.24.6.2526-2535.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Np95 Is a Histone-Binding Protein Endowed with Ubiquitin Ligase Activity

Elisabetta Citterio,1,2,{dagger} Roberto Papait,1,3,{dagger} Francesco Nicassio,1,2 Manuela Vecchi,1 Paola Gomiero,3 Roberto Mantovani,4 Pier Paolo Di Fiore,1,2,5* and Ian Marc Bonapace1,3

Istituto FIRC di Oncologia Molecolare, 20139 Milan,1 Istituto Europeo di Oncologia, 20141 Milan,2 Dipartimento di Biologia Strutturale e Funzionale, Università dell'Insubria, 21502 Varese,3 Dipartimento di Genetica e Biologia dei Microorganismi, Università degli Studi di Milano, 20133 Milan,4 Dipartimento di Medicina, Chirurgia ed Odontoiatria, Università di Milano, 20112 Milan, Italy5

Received 1 October 2003/ Returned for modification 9 November 2003/ Accepted 9 December 2003

Np95 is an important determinant in cell cycle progression. Its expression is tightly regulated and becomes detectable shortly before the entry of cells into S phase. Accordingly, Np95 is absolutely required for the G1/S transition. Its continued expression throughout the S/G2/M phases further suggests additional roles. Indeed, Np95 has been implicated in DNA damage response. Here, we show that Np95 is tightly bound to chromatin in vivo and that it binds to histones in vivo and in vitro. The binding to histones is direct and shows a remarkable preference for histone H3 and its N-terminal tail. A novel protein domain, the SRA-YDG domain, contained in Np95 is indispensable both for the interaction with histones and for chromatin binding in vivo. Np95 contains a RING finger. We show that this domain confers E3 ubiquitin ligase activity on Np95, which is specific for core histones, in vitro. Finally, Np95 shows specific E3 activity for histone H3 when the endogenous core octamer, coimmunoprecipitating with Np95, is used as a substrate. Histone ubiquitination is an important determinant in the regulation of chromatin structure and gene transcription. Thus, the demonstration that Np95 is a chromatin-associated ubiquitin ligase suggests possible molecular mechanisms for its action as a cell cycle regulator.

* Corresponding author. Mailing address: IFOM, The FIRC Institute for Molecular Oncology, Via Adamello 16, 20139 Milan, Italy. Phone: 39-02-574303247. Fax: 39-02-574303231. E-mail: difiore{at}ifom-firc.it

{dagger} E.C. and R.P. contributed equally to this work.

Molecular and Cellular Biology, March 2004, p. 2526-2535, Vol. 24, No. 6
0022-538X/04/$08.00+0     DOI: 10.1128/MCB.24.6.2526-2535.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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