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Molecular and Cellular Biology, September 2002, p. 6509-6520, Vol. 22, No. 18
0270-7306/02/$04.00+0     DOI: 10.1128/MCB.22.18.6509-6520.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

A Mammalian Bromodomain Protein, Brd4, Interacts with Replication Factor C and Inhibits Progression to S Phase

Tetsuo Maruyama,1,{dagger} Andrea Farina,1 Anup Dey,1 JaeHun Cheong,1,{ddagger} Vladimir P. Bermudez,2 Tomohiko Tamura,1 Selvaggia Sciortino,1 Jon Shuman,3 Jerard Hurwitz,2 and Keiko Ozato1*

Laboratory of Molecular Growth Regulation, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892-2753,1 Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, Maryland 20852,3 Department of Molecular Biology and Virology, Memorial Sloan-Kettering Cancer Center, New York, New York 100212

Received 31 January 2002/ Returned for modification 18 March 2002/ Accepted 18 June 2002

Brd4 belongs to the BET family of nuclear proteins that carry two bromodomains implicated in the interaction with chromatin. Expression of Brd4 correlates with cell growth and is induced during early G1 upon mitogenic stimuli. In the present study, we investigated the role of Brd4 in cell growth regulation. We found that ectopic expression of Brd4 in NIH 3T3 and HeLa cells inhibits cell cycle progression from G1 to S. Coimmunoprecipitation experiments showed that endogenous and transfected Brd4 interacts with replication factor C (RFC), the conserved five-subunit complex essential for DNA replication. In vitro analysis showed that Brd4 binds directly to the largest subunit, RFC-140, thereby interacting with the entire RFC. In line with the inhibitory activity seen in vivo, recombinant Brd4 inhibited RFC-dependent DNA elongation reactions in vitro. Analysis of Brd4 deletion mutants indicated that both the interaction with RFC-140 and the inhibition of entry into S phase are dependent on the second bromodomain of Brd4. Lastly, supporting the functional importance of this interaction, it was found that cotransfection with RFC-140 reduced the growth-inhibitory effect of Brd4. Taken as a whole, the present study suggests that Brd4 regulates cell cycle progression in part by interacting with RFC.

* Corresponding author. Mailing address: Laboratory of Molecular Growth Regulation, National Institute of Child Health and Human Development, National Institutes of Health, Bldg. 6, Rm. 2A01, Bethesda, MD 20892-2753. Phone: (301) 496-9184. Fax: (301) 480-9354. E-mail: ozatok{at}nih.gov.

{dagger} Present address: Department of Obstetrics and Gynecology, School of Medicine, Keio University, Shinjuku-ku, Tokyo 160-8582, Japan.

{ddagger} Present address: Center for Ligand & Transcription, Chonnam National University, Kwangju 500-757, Korea.

Molecular and Cellular Biology, September 2002, p. 6509-6520, Vol. 22, No. 18
0022-538X/02/$04.00+0     DOI: 10.1128/MCB.22.18.6509-6520.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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