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Molecular and Cellular Biology, April 2001, p. 2918-2932, Vol. 21, No. 8
0270-7306/01/$04.00+0 DOI: 10.1128/MCB.21.8.2918-2932.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.
RBP1 Recruits the mSIN3-Histone Deacetylase Complex to the Pocket
of Retinoblastoma Tumor Suppressor Family Proteins Found in Limited
Discrete Regions of the Nucleus at Growth Arrest
Albert
Lai,1
Brian K.
Kennedy,2
David A.
Barbie,2
Nicholas R.
Bertos,3
Xiang Jiao
Yang,3
Marie-Christine
Theberge,1
Shih-Chang
Tsai,4
Edward
Seto,4
Yi
Zhang,5
Andrei
Kuzmichev,6
William S.
Lane,7
Danny
Reinberg,6
Ed
Harlow,2 and
Philip E.
Branton1,8,*
Departments of Biochemistry1 and
Oncology8 and Molecular Oncology
Group, Department of Medicine,3 McGill
University, Montreal, Quebec, Canada H3G 1Y6; MGH Cancer
Center, Charlestown, Massachusetts 021292;
Howard Hughes Medical Institute, Division of Nucleic Acids
Enzymology, Department of Biochemistry, University of Medicine and
Dentistry of New Jersey, Robert Wood Johnson Medical School,
Piscataway, New Jersey 088546;
Lineberger Comprehensive Cancer Center, Department of
Biochemistry and Biophysics, University of North Carolina at Chapel
Hill, Chapel Hill, North Carolina 27599-72955;
H. Lee Moffitt Cancer Center and Research Institute,
Molecular Oncology Program, University of South Florida, Tampa,
Florida 336124; and Harvard
Microchemistry Facility, Harvard University, Cambridge,
Massachusetts 021387
Received 31 August 2000/Returned for modification 11 October
2000/Accepted 16 January 2001
Retinoblastoma (RB) tumor suppressor family pocket proteins induce
cell cycle arrest by repressing transcription of E2F-regulated genes
through both histone deacetylase (HDAC)-dependent and -independent mechanisms. In this study we have identified a stable complex that
accounts for the recruitment of both repression activities to the
pocket. One component of this complex is RBP1, a known pocket-binding
protein that exhibits both HDAC-dependent and -independent repression
functions. RB family proteins were shown to associate via the pocket
with previously identified mSIN3-SAP30-HDAC complexes containing
exclusively class I HDACs. Such enzymes do not interact directly with
RB family proteins but rather utilize RBP1 to target the pocket. This
mechanism was shown to account for the majority of RB-associated HDAC
activity. We also show that in quiescent normal human cells this entire
RBP1-mSIN3-SAP30-HDAC complex colocalizes with both RB family members
and E2F4 in a limited number of discrete regions of the nucleus that in
other studies have been shown to represent the initial origins of DNA
replication following growth stimulation. These results suggest that RB
family members, at least in part, drive exit from the cell cycle by
recruitment of this HDAC complex via RBP1 to repress transcription from
E2F-dependent promoters and possibly to alter chromatin structure at
DNA origins.
*
Corresponding author. Mailing address: Department of
Biochemistry, McGill University, McIntyre Medical Building, 3655 Drummond St., Montreal, Quebec, Canada H3G 1Y6. Phone: (514) 398-7268. Fax: (514) 398-7384. E-mail: branton{at}med.mcgill.ca.
Molecular and Cellular Biology, April 2001, p. 2918-2932, Vol. 21, No. 8
0270-7306/01/$04.00+0 DOI: 10.1128/MCB.21.8.2918-2932.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.
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