Nicotinamide Uncouples Hormone-Dependent Chromatin Remodeling from Transcription Complex Assembly

Chromatin and Gene Expression Section, Laboratory of Molecular Carcinogenesis, NIEHS/NIH, 111 Alexander Drive, P.O. Box 12233 (MD D4-01), Research Triangle Park, NC 27709, USA.
Molecular and Cellular Biology (Impact Factor: 4.78). 02/2008; 28(1):30-9. DOI: 10.1128/MCB.01158-07
Source: PubMed


Sirtuins, homologs of the yeast SIR2 family, are protein deacetylases that require nicotinamide adenosine dinucleotide as
cofactor. To determine whether the sirtuin family of deacetylases is involved in progesterone receptor (PR)-mediated transcription,
the effect of sirtuin inhibitor, nicotinamide (NAM), was monitored in T47D breast cancer cells. NAM suppressed hormone-dependent
activation of PR-regulated genes in a dose-dependent manner. Surprisingly, NAM-mediated inhibition of PR-mediated transcription
occurs independently of SIRT1 and PARP1. Chromatin immunoprecipitation experiments did not show that PR binding nor that of
the coactivators CBP and SRC3 was compromised. Consistent with the recruitment of the BRG1 chromatin remodeling complex, promoter
chromatin remodeling still occurs despite NAM inhibition of PR transactivation. Rather, we show that this inhibition of transcription
is due to dramatic loss of recruitment of the basal transcriptional machinery to the promoter. These results show that NAM
uncouples promoter chromatin remodeling from transcription preinitiation complex assembly and suggest the existence of vital
NAM-regulated steps required for promoter chromatin remodeling and basal transcription complex communication.

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Available from: Trevor K Archer
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    • "Steroid hormone receptors, such as the estrogen (ER) and androgen receptors (AR), as well as the progesterone (PR), glucocorticoid (GR), and mineralocorticoid receptors (MR) are part of a large nuclear receptor family of eukaryotic transcription factors (Tsai & Omalley 1994, Mangelsdorf et al. 1995, Aoyagi & Archer 2008). Steroid hormone receptors play essential roles in numerous biological processes, such as homeostasis, metabolism, cell growth, and development (Tsai & Omalley 1994, Mangelsdorf et al. 1995, Chawla et al. 2001). "
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