Disease relevance of ADA2

• A selection for yeast mutants resistant to GAL4-VP16-induced toxicity previously identified two genes, ADA2 and ADA3, which may function as adaptors for some transcriptional activation domains and thereby facilitate activation [1].

High impact information on ADA2

• Both the 0.8- and 1.8-MD Gcn5-containing complexes cofractionate with Ada2 and are lost in gcn5delta, ada2delta, or ada3delta yeast strains, illustrating that these HAT complexes are bona fide native Ada-transcriptional adaptor complexes [2].
• This suggests that ADA2 and GCN5 are part of a heteromeric complex that mediates transcriptional activation [1].
• Previously it was shown that yeast ADA2 protein is necessary for the full activity of some activation domains, such as VP16 and GCN4, in vivo and in vitro [3].
• In addition, analysis of an ada2 rad6 deletion strain indicated that the SAGA acetyltransferase complex and Rad6 act in the same pathway to repress ARG1 in rich medium [4].
• In the absence of Ada2p, the elution profile of Tra1p shifted to a distinct peak [5].

Biological context of ADA2

• We show here that mutations in ADA2, ADA3, and GCN5, which are believed to encode subunits of a nuclear histone acetyltransferase complex, cause phenotypes strikingly similar to that of swi/snf mutants [6].
• Mutations in ADA2 or GCN5, encoding components of the ADA coactivator complex involved in histone acetylation, severely reduced LexA-ADR1-TAD activation of a LexA-lacZ reporter gene [7].
• Using an in vitro protein binding assay, ADA2 and GCN5 were found to specifically contact individual ADR1 TADs [7].
• Regulation of gene expression by glucose in Saccharomyces cerevisiae: a role for ADA2 and ADA3/NGG1 [8].
• The transcriptional coactivator ADA2 is an evolutionarily conserved component of histone acetyltransferase (HAT) complexes involved in chromatin remodeling and transcriptional regulation in eukaryotes [9].

Associations of ADA2 with chemical compounds

• Loss of either ADA2 or ADA3/NGG1 also affects a large number of genes and inhibits the rapid global increase in transcription that occurs in response to glucose [8].
• The data presented here, together with our earlier data on the function of dAda2b, provide evidence that related Ada2 proteins of Drosophila, together with Gcn5 HAT, are involved in the acetylation of specific lysine residues in the N-terminal tails of nucleosomal H3 and H4 [10].

Physical interactions of ADA2

• Moreover, we demonstrate that GCN5 binds to ADA2 both by the two-hybrid assay in vivo and by co-immunoprecipitation in vitro [1].
• The carboxyl-terminal domain of ADA3 alone suffices for heterotrimeric complex formation in vitro and activation of LexA-ADA2 in vivo [11].
• The not2::R165G also abrogated NOT2 ability to interact with ADA2 but had little effect on the integrity of the CCR4-NOT complex [12].

Enzymatic interactions of ADA2

• The anti-silencing effect of Gcn5p is abolished by a mutation that eliminated its HAT activity or by deleting the ADA2 gene encoding a structural component of Gcn5p-containing HAT complexes [13].

Regulatory relationships of ADA2

• A deletion of only the Ada2 SANT domain has exactly the same effect, strongly suggesting that Ada2 controls Gcn5 activity by virtue of its SANT domain [14].
• This ability of ADA2 to activate transcription is mediated by ADA3, a gene with properties similar to ADA2 [3].

Other interactions of ADA2

• Identification of native complexes containing the yeast coactivator/repressor proteins NGG1/ADA3 and ADA2 [15].
• Deletion of GCN5 or ADA2 reduces repair at MET16 [16].
• This suggests that a site required for ADA2p interaction lies between amino acids 308 and 373 and that ADA2p has a regulatory role in activation by GAL4p-NGG1p(1-373) [17].
• Alterations in NOT2 contacts to ADA2, therefore, do not necessarily result in effects on the CCR4-NOT complex nor result in severe growth defects [12].
• Although the activation domain of the yeast activator HAP4 is also highly negatively charged, its function is independent of at least one component of the adaptor complex, ADA2 [18].

Analytical, diagnostic and therapeutic context of ADA2

• The presence of another high molecular mass complex was supported by the separation of one of the NGG1p- and ADA2p-containing peak fractions by gel-filtration chromatography [15].
• Sequence analysis demonstrated the presence of an ADA2 homologue in each Plasmodium species selected for genome sequencing [9].

References