Histone proteins play structural and functional roles in all nuclear processes. They undergo different types of covalent modifications, defined in their ensemble as epigenetic because changes in DNA sequences are not involved. Histone acetylation emerges as a central switch that allows interconversion between permissive and repressive chromatin domains in terms of transcriptional competence. The mechanisms underlying the histone acetylation-dependent control of gene expression include a direct effect on the stability of nucleosomal arrays and the creation of docking sites for the binding of regulatory proteins. Histone acetyltransferases and deacetylases are, respectively, the enzymes devoted to the addition and removal of acetyl groups from lysine residues on the histone N-terminal tails. The enzymes exert fundamental roles in developmental processes and their deregulation has been linked to the progression of diverse human disorders, including cancer.

Genetic information is packaged in the highly dynamic nucleoprotein structure called chromatin. Many biological processes are regulated via post-translational modifications of key proteins. Acetylation of lysine residues at the N-terminal histone tails is one of the most studied covalent modifications influencing gene regulation in eukaryotic cells. This review focuses on the role of enzymes involved in controlling both histone and non-histone proteins acetylation levels in the cell, with particular emphasis on their effects on cancer.

We have analyzed at both low and high resolution the distribution of nucleosomes over the Saccharomyces cerevisiae ADH2 promoter region in its chromosomal location, both under repressing (high-glucose) conditions and during derepression. Enzymatic treatments (micrococcal nuclease and restriction endonucleases) were used to probe the in vivo chromatin structure during ADH2 gene activation. Under glucose-repressed conditions, the ADH2 promoter was bound by a precise array of nucleosomes, the principal ones positioned at the RNA initiation sites (nucleosome +1), at the TATA box (nucleosome -1), and upstream of the ADR1-binding site (UAS1) (nucleosome -2). The UAS1 sequence and the adjacent UAS2 sequence constituted a nucleosome-free region. Nucleosomes -1 and +1 were destabilized soon after depletion of glucose and had become so before the appearance of ADH2 mRNA. When the transcription rate was high, nucleosomes -2 and +2 also underwent rearrangement. When spheroplasts were prepared from cells grown in minimal medium, detection of this chromatin remodeling required the addition of a small amount of glucose. Cells lacking the ADR1 protein did not display any of these chromatin modifications upon glucose depletion. Since the UAS1 sequence to which Adr1p binds is located immediately upstream of nucleosome -1, Adr1p is presumably required for destabilization of this nucleosome and for aiding the TATA-box accessibility to the transcription machinery.

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Depletion of any of the five essential proteins Lsm2p to Lsm5p and Lsm8p leads to strong accumulation of all tested unspliced pre-tRNA species, as well as accumulation of 5 and 3 unprocessed species. Aberrant 3-extended pre-tRNAs were detected, presumably due to stabilization of transcripts that fail to undergo correct transcription termination, and the accumulation of truncated tRNA fragments was also observed. Tandem affinity purification-tagged Lsm3p was associated with pre-tRNA primary transcripts and, less efficiently, with other unspliced pre-tRNA intermediates but not mature tRNAs. Association of the Saccharomyces cerevisiae La homologue Lhp1p with pre-tRNAs was reduced approximately threefold on depletion of Lsm3p or Lsm5p. The association of Lhp1p with larger RNA polymerase III transcripts, pre-RNase P RNA and the signal recognition particle RNA (scR1), was more drastically reduced. The impaired pre-tRNA processing seen on Lsm depletion is not, however, due solely to reduced Lhp1p association as evidenced by analysis of lhp1-⌬ strains depleted of Lsm3p or Lsm5p. These data are consistent with roles for an Lsm complex as a chaperone that facilitates the efficient association of pre-tRNA processing factors with their substrates.The U1, U2, U4, and U5 snRNAs associate with the seven Sm proteins (20), which form a closed ring structure (23). In contrast, U6 snRNA associates with seven related proteins, Lsm2p (Lsm stands for "like Sm") to Lsm8p (8,17,29,34,40,41,44), which also form a heptameric ring structure (1, 2, 7). The Lsm2p-Lsm8p complex is involved in pre-mRNA splicing, probably by facilitating biogenesis of the U6 snRNP and its structural rearrangement during spliceosome assembly. The related Lsm1p-Lsm7p complex associates with cytoplasmic mRNA decay factors and functions in mRNA decapping and degradation (4,5,19,45). The Lsm2p-Lsm8p complex binds U6 snRNA via the 3Ј poly(U) tract (1, 2). Newly synthesized U6 also binds Lhp1p (La-homologous protein), the Saccharomyces cerevisiae homologue of the human La phosphoprotein, which protects the RNA against degradation (34).Recent analyses have identified Sm-like proteins in both the domains Archaea and Bacteria (2,7,30,31,47,52). Since these organisms lack both the U6 snRNA and capped mRNAs, this suggested that the ancestral Sm-like proteins had different functions in RNA metabolism. Indeed, evidence has been presented for their association with the RNA component of RNase P in Archaea and with small regulatory RNAs in Escherichia coli, where the Sm-like Hfq protein was proposed previously to act as a chaperone facilitating RNA-RNA interactions (30, 47, 52). We have therefore investigated possible additional roles for the eukaryotic Lsm proteins.Poly(U) tracts are present in all RNA polymerase III (Pol-III) transcribed RNAs, including pre-tRNAs, pre-P RNA (the RNA component of RNase P), pre-5S rRNA, and scR1 (the RNA component of signal recognition particle), all of which also bind Lhp1p/La (6,37,38,43,51). Here we show that Lsm proteins associate with som...