The SAGA complex is a conserved histone acetyltransferase-coactivator that regulates gene expression in Saccharomyces cerevisiae. SAGA contains a number of subunits known to function in transcription including Spt and Ada proteins, the Gcn5 acetyltransferase, a subset of TATA-binding-protein-associated factors (TAF II s), and Tra1. Here we report the identification of SLIK (SAGA-like), a complex related in composition to SAGA. Notably SLIK uniquely contains the protein Rtg2, linking the function of SLIK to the retrograde response pathway. Yeast harboring mutations in both SAGA and SLIK complexes displays synthetic phenotypes more severe than those of yeast with mutation of either complex alone. We present data indicating that distinct forms of the SAGA complex may regulate specific subsets of genes and that SAGA and SLIK have multiple partly overlapping activities, which play a critical role in transcription by RNA polymerase II.The histone components of chromatin are subjected to several posttranslational modifications including acetylation, phosphorylation, ubiquitination, methylation, and ADP-ribosylation that regulate their function and that of the corresponding DNA sequences (16,56). Of these modifications the acetylation and deacetylation of the ε-amino groups of the conserved lysine residues present in the amino terminal tails of all four core histones have long been linked to transcriptional activity and have been the most intensively studied histone modification. The acetylation of histones is catalyzed by histone acetyltransferases (HATs), which are often found to be associated with large multisubunit protein complexes that contain components with identity or homology to known regulators of transcription (17,47).The first transcription-related type A HAT to be identified was the Tetrahymena p55 protein, a homologue of Saccharomyces cerevisiae Gcn5 (8). Gcn5 was originally identified through genetic screens as a transcriptional coactivator in yeast (23) and thus provided a strong foundation for the direct coupling of histone acetylation and transcriptional stimulation. Gcn5 has subsequently been identified as a component of high-molecular-weight acetyltransferase/transcriptional adaptor complexes from both yeast and human cells (19,25,37,40,43,45,49,50). The association of Gcn5 in multiprotein complexes potentiates its nucleosomal HAT activity (3,19,43,49,58,59), important for the transcriptional stimulatory activity of these complexes from chromatin templates in vitro and in vivo (31,54,61). In addition this association bestows upon Gcn5 an expanded lysine specificity (3, 20, 52, 65). Thus, a common feature of HAT proteins with proposed coactivator function is their frequent association with other subunits that potentiate catalytic function and/or mediate interactions with activators or basal factors (7).We have previously identified Gcn5 as a component of the 1.8-MDa transcriptional regulatory complex SAGA (Spt-AdaGcn5-acetyltransferase). In this complex Gcn5 is associated with the Ada1 to Ada3 member...