Abstract: ABSTRACT: BACKGROUND: Tra1 is an essential 437-kDa component of the Saccharomyces cerevisiae SAGA/SLIK and NuA4 histone acetyltransferase complexes. It is a member of a group of key signaling molecules that share a carboxyl-terminal domain related to phosphatidylinositol-3-kinase but unlike many family members, it lacks kinase activity. To identify genetic interactions for TRA1 and provide insight into its function we have performed a systematic genetic array analysis (SGA) on tra1SRR3413, an allele that is defective in transcriptional regulation. RESULTS: The SGA analysis revealed 114 synthetic slow growth/lethal (SSL) interactions for tra1SRR3413. The interacting genes are involved in a range of cellular processes including gene expression, mitochondrial function, and membrane sorting/protein trafficking. In addition many of the genes have roles in the cellular response to stress. A hierarchal cluster analysis revealed that the pattern of SSL interactions for tra1SRR3413 most closely resembles deletions of a group of regulatory GTPases required for membrane sorting/protein trafficking. Deletion of SMI1, one of the genes identified in the SGA analysis and with defined roles in cell wall function and stress response shares several phenotypes with tra1SRR3413. Also consistent with a role for Tra1 in cellular stress, the sensitivity of the tra1SRR3413 strain to calcofluor white was enhanced by the protein kinase inhibitor staurosporine, a phenotype shared with the ada components of the SAGA/SLIK complex. Through analysis of a GFP-Tra1 fusion we show that Tra1 is principally localized to the nucleus. CONCLUSIONS: We have demonstrated a genetic association of Tra1 with the processes of membrane sorting and protein trafficking. The identity of the SSL genes also connects Tra1 with cellular stress, a result confirmed by the sensitivity of the tra1SRR3413 strain to a variety of stress conditions. Based upon the nuclear localization of GFP-Tra1 and the finding that deletion of the ada components of the SAGA complex result in similar phenotypes as tra1SRR3413, we suggest that the effects of tra1SRR3413 are mediated, at least in part, through its role in the SAGA complex.