Histone H3 Ser10 phosphorylation-independent function of Snf1 and Reg1 proteins rescues a gcn5- mutant in HIS3 expression

401 BCH Building, Department of Biochemistry and Molecular Biology, Michigan State University, East Lansing, MI 48824. .
Molecular and Cellular Biology (Impact Factor: 4.78). 01/2006; 25(23):10566-79. DOI: 10.1128/MCB.25.23.10566-10579.2005
Source: PubMed


Gcn5 protein is a prototypical histone acetyltransferase that controls transcription of multiple yeast genes. To identify
molecular functions that act downstream of or in parallel with Gcn5 protein, we screened for suppressors that rescue the transcriptional
defects of HIS3 caused by a catalytically inactive mutant Gcn5, the E173H mutant. One bypass of Gcn5 requirement gene (BGR) suppressor was mapped to the REG1 locus that encodes a semidominant mutant truncated after amino acid 740. Reg1(1-740) protein does not rescue the complete
knockout of GCN5, nor does it suppress other gcn5− defects, including the inability to utilize nonglucose carbon sources. Reg1(1-740) enhances HIS3 transcription while HIS3 promoter remains hypoacetylated, indicating that a noncatalytic function of Gcn5 is targeted by this suppressor protein.
Reg1 protein is a major regulator of Snf1 kinase that phosphorylates Ser10 of histone H3. However, whereas Snf1 protein is
important for HIS3 expression, replacing Ser10 of H3 with alanine or glutamate neither attenuates nor augments the BGR phenotypes. Overproduction of Snf1 protein also preferentially rescues the E173H allele. Biochemically, both Snf1 and Reg1(1-740)
proteins copurify with Gcn5 protein. Snf1 can phosphorylate recombinant Gcn5 in vitro. Together, these data suggest that Reg1
and Snf1 proteins function in an H3 phosphorylation-independent pathway that also involves a noncatalytic role played by Gcn5

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    • "Surprisingly, pre-IL-1α significantly rescued growth defects of the snf1-108 strain but not the snf1Δ mutant strain on glycerol agar plates containing 3-AT. These results provide another evidence supporting our structural model, and because of the known role of Snf1 and SAGA complex in the regulation of transcription initiation at HIS3 promoter [48], [52], point to the possibility of a competition between pre-IL-1α and Snf1/AMPK for the same binding sites in HAT complexes (Figure 4). "
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    • "Chromatin decompaction and access to specific genomic loci are controlled by post-translational histone modifications, which occur in a dynamic, cell-specific manner in response to external stimuli and affect histone-DNA linkage (16,17). The main post-translational histone modifications described so far include acetylation of histone H3 Lys9 and Lys14, and acetylation of histone H4 Lys5 (18,19) by histone acetyltransferases. In contrast, histone deacetylases (HDACs) catalyze deacetylation. "
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    • "This interaction may also play a direct role to regulate the Gcn5's HAT activity, thus contributing to the establishment or maintenance of active chromatin. Intriguingly, several studies have also implicated that Gcn5 preferentially acetylate histone H3 that is phosphorylated at S10 [76] [77] [78] [79] [80] [81], suggesting the role of histone H3 phosphorylation on SAGA's HAT activity. Together, these studies demonstrate that the interaction of SAGA with activator drives its recruitment, and subsequently, histone covalent modification leads to its stabilization onto the promoter. "
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