Human STAGA Complex Is a Chromatin-Acetylating Transcription Coactivator That Interacts with Pre-mRNA Splicing and DNA Damage-Binding Factors In Vivo

Abstract

GCN5 is a histone acetyltransferase (HAT) originally identified inIn eukaryotes, genomic DNA is packaged by histones into nucleosomes that further fold to form higher-order chromatin structures. Eukaryotic cells have evolved two major enzymatic mechanisms to modify chromatin structure: (i) ATP-dependent nucleosome remodeling by multiprotein complexes that use the energy of ATP hydrolysis to alter the association of core histones with DNA and (ii) covalent modifications of core histones, including acetylation, that regulate core histone interactions with either DNA, adjacent nucleosomes, or other regulatory proteins (reviewed in references 7, 39, 64, and 74).Reversible acetylation of specific lysine residues within the N-terminal tails of nucleosomal core histones has long been correlated with changes in chromatin that occur during transcription, replication, and DNA repair in vivo (reviewed in references 7, 61, and 65). Significant progress in understanding the role of nuclear histone acetylation came from the findings that the Saccharomyces cerevisiae transcription coactivator GCN5, and more recently other yeast and metazoan transcription cofactors, are histone acetyltransferases (HATs) and that several transcription corepressor complexes have histone deacetylases as integral subunits (reviewed in references 4 and 10). HATs differ in substrate specificity and may also modify nonhistone regulatory proteins, as originally demonstrated for p53 acetylation by p300 (27). Many nuclear HATs are also part of large multiprotein assemblies. These include yeast SAGA (SPT-ADA-GCN5 acetylase), ADA, NuA3, NuA4, and Elongator complexes, yeast and metazoan TFIID complexes, and human TFTC (TATA-binding protein [TBP]-free TBP-associated factor II [TAF II ]-containing complex), PCAF, STAGA (SPT3-TAF II 31-GCN5L acetylase), TIP60, and TFIIIC complexes (reviewed in references 10 and 24).In yeast, GCN5 is an integral subunit of at least two distinct multiprotein HAT complexes, the ADA and SAGA complexes, that acetylate histones H3 and H2B within nucleosomes (25). The yeast SAGA complex is composed of (i) ADA adapter (coactivator) proteins (ADA1, ADA2, ADA3, ADA4 [GCN5], and ADA5 [SPT20]), (ii) SPT proteins (SPT3, SPT7, SPT8, and SPT20 [ADA5]), (iii) a subset of the yeast TAF II s (yTAF II s) (yTAF II 17/20, yTAF II 25, yTAF II 60, yTAF II 61/68, and yTAF II 90), and (iv) a protein, Tra1, that is structurally related to members of the ATM/DNA-PK/phosphatidylinositol 3-kinase family (reviewed in references 10, 24, and 78). The ADA complex shares GCN5, ADA2, and ADA3 with SAGA but lacks all other SAGA subunits and has ADA-specific components (20). The SAGA complex, but not the ADA complex,

Orchestration of chromatin-based processes: mind the TRRAP

“…TFTC complex containing GCN5 HAT was found to preferentially bind UV-irradiated DNA and to acetylate histone H3 in nucleosomes assembled on UV-damaged DNA (Brand et al, 2001). These findings were supported by studies showing that STAGA, another GCN5-containing complex, interacts with UV-damaged-DNA-binding protein involved in the repair of DNA single-strand breaks (Martinez et al, 2001) and that NuA4 participates in NHEJ repair by specific recruitment to DNA DSBs (Bird et al, 2002). In addition, mutations in Yng2, a component of NuA4 complex, result in inefficient repair of DNA damage caused by genotoxic agents that induce replication fork stall, consistent with the role of Tip60/ NuA4 in HR (Choy and Kron, 2002).…”

“…TRRAP/Tra1-containing HAT complexes from the GNAT family include SAGA (Spt/Ada/Gcn5/acetyltransferase) (Grant et al, 1998), SLIK (SAGA-like) (Pray- and SALSA (SAGA altered, Spt8 absent) (Sterner et al, 2002) from yeast. The STAGA (SPT3-TAF II 31-GCN5L acetylase) (Martinez et al, 2001) and TFTC (TATA-binding protein-free) TAF(II) (Brand et al, 1999) are TRRAP, GCN5-and PCAF-(p300/CBP-associated factor) containing complexes in mammalian cells. The NuA4 (nucleosomal acetyltransferase of histone H4) complex and its mammalian equivalent Tip60 are TRRAP/Tra1-containing HAT complexes from the MYST family (Allard et al, 1999;Ikura et al, 2000).…”

Other Proteins Interacting with XP Proteins

“…16 XPE interacts with a variety of proteins to modulate cellular responses to DNA damage. Interactions between XPE and the CBP/p300 17,18 and STAGA 18,19 chromatin remodeling complexes also are critical for the efficient removal of damage by the GG-NER pathway. These complexes acetylate histones, thereby relaxing the local chromatin superstructures to allow access to the DNA for processes such as repair or transcription.…”

Spliceosome and other novel mutations in chronic lymphocytic leukemia and myeloid malignancies

“…37 The lack of SF3B1 may impair PRC1 function 18 and the SPT3-TAFII31-GCN5L acetylase complex may also interact with splice factors. 38 Mutations affecting 'splice genes' may therefore alter either upstream the efficiency of transcription or downstream the kinetics of mRNA export to the cytoplasm and/or lead to RNA degradation. 39 It is conceivable that the rates of transcription, splicing and transport to the cytoplasm are linked and influence chromatin structure.…”