CIR, a corepressor linking the DNA binding factor CBF1 to the histone deacetylase complex

CIR, a corepressor linking the DNA binding factor CBF1 to the histone deacetylase complex

Molecular Virology Laboratories, Department of Pharmacology and Molecular Sciences and Department of Oncology, Johns Hopkins School of Medicine, 725 North Wolfe Street, Baltimore, MD 21205

Edited by Stephen L. McKnight, University of Texas Southwestern Medical Center, Dallas, TX, and approved October 23, 1998 (received for review July 1, 1998)

Abstract

CBF1 is a member of the CSL family of DNA binding factors, which mediate either transcriptional repression or transcriptional activation. CSL proteins play a central role in Notch signaling and in Epstein–Barr virus-induced immortalization. Notch is a transmembrane protein involved in cell-fate decisions, and the cytoplasmic domain of Notch (NotchIC) targets CBF1. The Epstein–Barr virus-immortalizing protein EBNA2 activates both cellular and viral gene expression by targeting CBF1 and mimicking NotchIC. We have examined the mechanism of CBF1-mediated repression and show that CBF1 binds to a unique corepressor, CBF1 interacting corepressor (CIR). A CIR homolog is encoded by Caenorhabditis elegans, indicating that CIR is evolutionarily conserved. Two CBF1 mutants that were unable to bind CIR did not function as repressors, suggesting that targeting of CIR to CBF1 is an important component of repression. When expressed as a Gal4 fusion protein, CIR repressed reporter gene expression. CIR binds to histone deacetylase and to SAP30 and serves as a linker between CBF1 and the histone deacetylase complex.

Footnotes

↵ * To whom correspondence and requests for materials should be addressed. e-mail: Diane_Hayward{at}qmail.bs.jhu.edu.
This paper was submitted directly (Track II) to the Proceedings Office.
Data deposition: The sequence reported in this paper has been deposited in the GenBank database (accession no. AF098297).
ABBREVIATIONS:

EBV,

Epstein–Barr virus;

CIR,

CBF1-interacting corepressor;

HDAC,

histone deacetylase;

TNFR,

tumor necrosis factor receptor;

EBNA,

EBV-encoded nuclear antigen;

IC,

intracellular domain;

hCIR,

human CIR, TK, thymidine kinase;

luc,

luciferase;

CMV,

cytomegalovirus