The acetylation of spermidine catalyzed by P/CAF regulates its acetyltransferase activity versus histones

Transcriptional regulation in eukaryotes occurs within a chromatin setting and is strongly inhibited by nucleosomal barriers imposed by histone proteins. Among the well-known covalent modifications of chromatin, the reversible acetylation of specific lysine residues of histones, catalyzed by several acetyltransferase and deacetylases, has been linked to many biological processes including transcriptional regulation. Indeed, many transcriptional coactivators possess histone acetyltransferase (HAT) activity (1). Functional interactions between HAT and polyamines have been previously reported. In particular, it has been shown that polyamines facilitate oligomerization of nucleosomal arrays in vitro. Moreover, polyamine-mediated chromatin condensation has also been shown to require intact core histone N-terminal domains and is inhibited by histone hyperacetylation (2). PCAF is an evolutionarily conserved HAT that has histones H3 and H4 as targets. In order to understand the possible functional relationship existing between histones and polyamines, we tested the effect played by spermidine over PCAF acetylating activity versus histone H3. We observed that spermidine inhibits histone H3 acetylation in vitro and remarkably, we found that at very low spermidine concentrations (5-10 μM) PCAF can directly acetylate spermidine. Interestingly, the biosynthesis of N-acetylspermidine by PCAF was observed both in the absence and in the presence of equimolecular concentrations of histone H3. Although PCAF is able to acetylate histones and various proteins we think that spermidine may be a PCAF additional target and that its acetylation could be a fine mechanism regulating polyamines/acetyl-polyamines availability in biological systems. Recently, spermidine has been implicated in the induction of cell autophagy and promotion of longevity in several organisms and cell types. Polyamine-induced suppression of necrosis and the consequently enhanced longevity have been awarded to deacetylated state of histone H3, as result of inhibition of HAT by spermidine (5).