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Molecular and Cellular Biology, April 2009, p. 2181-2192, Vol. 29, No. 8
0270-7306/09/$08.00+0     doi:10.1128/MCB.01517-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Association of C-Terminal Ubiquitin Hydrolase BRCA1-Associated Protein 1 with Cell Cycle Regulator Host Cell Factor 1{triangledown}

Shahram Misaghi,1 Søren Ottosen,5 Anita Izrael-Tomasevic,2 David Arnott,2 Mohamed Lamkanfi,1 James Lee,3 Jinfeng Liu,4 Karen O'Rourke,1 Vishva M. Dixit,1* and Angus C. Wilson5*

Physiological Chemistry Department,1 Protein Chemistry Department,2 Molecular Biology Department,3 Bioinfomatics Department, Genentech, Inc., 1 DNA Way, South San Francisco, California 94080,4 Department of Microbiology and NYU Cancer Institute, New York University School of Medicine, New York, New York 100165

Received 29 September 2008/ Returned for modification 27 October 2008/ Accepted 26 January 2009

Protein ubiquitination provides an efficient and reversible mechanism to regulate cell cycle progression and checkpoint control. Numerous regulatory proteins direct the addition of ubiquitin to lysine residues on target proteins, and these are countered by an army of deubiquitinating enzymes (DUBs). BRCA1-associated protein-1 (Bap1) is a ubiquitin carboxy-terminal hydrolase and is frequently mutated in lung and sporadic breast tumors. Bap1 can suppress growth of lung cancer cells in athymic nude mice and this requires its DUB activity. We show here that Bap1 interacts with host cell factor 1 (HCF-1), a transcriptional cofactor found in a number of important regulatory complexes. Bap1 binds to the HCF-1 β-propeller using a variant of the HCF-binding motif found in herpes simplex virus VP16 and other HCF-interacting proteins. HCF-1 is K48 and K63 ubiquitinated, with a major site of linkage at lysines 1807 and 1808 in the HCF-1C subunit. Expression of a catalytically inactive version of Bap1 results in the selective accumulation of K48 ubiquitinated polypeptides. Depletion of Bap1 using small interfering RNA results in a modest accumulation of HCF-1C, suggesting that Bap1 helps to control cell proliferation by regulating HCF-1 protein levels and by associating with genes involved in the G1-S transition.

* Corresponding author. Mailing address for Vishva M. Dixit: Department of Physiological Chemistry, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080. Phone: (650) 225-1312. Fax: (650) 225-6127. E-mail: dixit.vishva{at}gene.com. Mailing address for Angus C. Wilson: Department of Microbiology, NYU School of Medicine, 550 First Ave., New York, NY 10016. Phone: (212) 263-0206. Fax: (212) 263-8276. E-mail: angus.wilson{at}med.nyu.edu

{triangledown} Published ahead of print on 2 February 2009.

Molecular and Cellular Biology, April 2009, p. 2181-2192, Vol. 29, No. 8
0270-7306/09/$08.00+0     doi:10.1128/MCB.01517-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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