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Acetylation in nuclear receptor signaling and the role of sirtuins.

It has been known since the early 1970s that nuclear receptor complexes bind DNA in association with coregulatory proteins. Characterization of these nuclear receptor coregulators has revealed diverse enzymatic activities that temporally and spatially coordinate nuclear receptor activity within the context of local chromatin in response to diverse hormone signals. Chromatin-modifying proteins, which dictate the higher-order chromatin structure in which DNA is packaged, in turn orchestrate orderly recruitment of nuclear receptor complexes. Modifications of histones include acetylation, methylation, phosphorylation, ubiquitylation, sumoylation, ADP ribosylation, deimination, and proline isomerization. At this time, we understand how a subset of these modifications regulates nuclear receptor signaling. However, the effects, particularly of acetylation and demethylation, are profound. The finding that nuclear receptors are directly acetylated and that acetylation in turn directly regulates contact-independent growth has broad therapeutic implications. Studies over the past 7 yr have led to the understanding that nuclear receptor acetylation is a conserved function, regulating diverse nuclear receptor activity. Furthermore, we now know that acetylation of multiple and distinct substrates within nuclear receptor signaling pathways, form an acetylation signaling network from the cell surface to the nucleus. The finding that nicotinamide adenine dinucleotide (NAD)-dependent histone deacetylases, the sirtuins, are capable of deacetylating nuclear receptors provides a new level of complexity in the control of nuclear receptor activity in which local intracellular concentrations of NAD may regulate nuclear receptor physiology.