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Vol. 14, No. 1, pp. 45-54, January 1, 2000
1 Division of Endocrinology, Diabetes, and Metabolism,
Departments of Medicine and Genetics, and The Penn Diabetes Center,
University of Pennsylvania School of Medicine, Philadelphia,
Pennsylvania 19104 USA; 2 The Wellcome/Cancer
Research Campaign (CRC) Institute, CB21QR Cambridge UK
Transcriptional repression mediated by corepressors N-CoR and SMRT
is a critical function of nuclear hormone receptors, and is
dysregulated in human myeloid leukemias. At the present time, these
corepressors are thought to act exclusively through an
mSin3/HDAC1 complex. Surprisingly, however, numerous
biochemical studies have not detected N-CoR or SMRT in mSin3- and
HDAC1-containing complexes. Each corepressor contains multiple
repression domains (RDs), the significance of which is unknown. Here we
show that these RDs are nonredundant, and that one RD, which is
conserved in N-CoR and SMRT, represses transcription by interacting
directly with class II HDAC4 and HDAC5. Endogenous N-CoR and SMRT each
associate with HDAC4 in a complex that does not contain mSin3A or
HDAC1. This is the first example of a single corepressor utilizing
distinct domains to engage multiple HDAC complexes. The alternative
HDAC complexes may mediate specific repression pathways in normal as well as leukemic cells.
[Key Words: mSin3; HDAC1; HDAC4; HDAC5; chromatin; nuclear receptors; N-CoR; SMRT]
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