Orchestration of chromatin-based processes: mind the TRRAP

Abstract

Chromatin modifications at core histones including acetylation, methylation, phosphorylation and ubiquitination play an important role in diverse biological processes. Acetylation of specific lysine residues within the N terminus tails of core histones is arguably the most studied histone modification; however, its precise roles in different cellular processes and how it is disrupted in human diseases remain poorly understood. In the last decade, a number of histone acetyltransferases (HATs) enzymes responsible for histone acetylation, has been identified and functional studies have begun to unravel their biological functions. The activity of many HATs is dependent on HAT complexes, the multiprotein assemblies that contain one HAT catalytic subunit, adapter proteins, several other molecules of unknown function and a large protein called TRansformation/tRanscription domain-Associated Protein (TRRAP). As a common component of many HAT complexes, TRRAP appears to be responsible for the recruitment of these complexes to chromatin during transcription, replication and DNA repair. Recent studies have shed new light on the role of TRRAP in HAT complexes as well as mechanisms by which it mediates diverse cellular processes. Thus, TRRAP appears to be responsible for a concerted and context-dependent recruitment of HATs and coordination of distinct chromatin-based processes, suggesting that its deregulation may contribute to diseases. In this review, we summarize recent developments in our understanding of the function of TRRAP and TRRAP-containing HAT complexes in normal cellular processes and speculate on the mechanism underlying abnormal events that may lead to human diseases such as cancer.

The SAGA continues: expanding the cellular role of a transcriptional co-activator complex

“…Thus TRRAP's role in oncogenic transformation may be achieved primarily through aberrant gene expression due to avhieved improper STAGA recruitment. The role of TRRAP in chromatin-based processes is further discussed in a separate article in this issue (Murr et al, 2007).…”

Ethylnitrosourea‐induced thymus‐defective mutants identify roles ofKIAA1440, TRRAP, andSKIV2L2in teleost organ development

“…TRRAP, a histone acetyltransferase cofactor, functions as an essential component of most histone acetyltransferase complexes that regulate chromatin remodeling and gene expression [31][32][33]. Null mutation of TRRAP in mice results in periimplantation lethality due to the inhibition of blastocyst proliferation [34].…”

“…KIAA1440 in medaka consists of 2185 amino acid residues, whereas the awb mutation presumably produces a protein with 1141 amino acid residues of KIAA1440 N-terminus and 28 amino acid residues derived from the intron. As no domain structures are known in KIAA1440, it is unclear how incompetent the presumed awb-allele-derived KIAA1440 mutant protein is structurally and functionally.TRRAP, a histone acetyltransferase cofactor, functions as an essential component of most histone acetyltransferase complexes that regulate chromatin remodeling and gene expression [31][32][33]. Null mutation of TRRAP in mice results in periimplantation lethality due to the inhibition of blastocyst proliferation [34].…”

The multi-tasking P-TEFb complex

“…Brd4 can also interact with the mediator complex and may help recruit RNAPII to chromatin [29]. The budding yeast homolog of Brd4, Bdf1, binds preferentially to chromatin acetylated by the NuA4/Tip60 HAT complex [30], which is recruited to genes through TRRAP, a direct target of many DNA-bound activators [31]. Importantly, Bdf1 also functions with the SWR-C chromatin remodeling complex to direct replication-independent exchange of H2A.Z histones at induced promoters [32 • ,33 • ].…”

“…Overexpression of the c-Myc transactivation domain enhances global levels of RNAPII Ser5P and Ser2P, and c-Myc can also bind to CDK7 [40 • ]. In addition to P-TEFb, c-Myc binds avidly to TRRAP, a pseudokinase PI3K family member that is a frequent target of acidic activators [31] and functions as a scaffold for both SAGA-type (H3-specific) and NuA4-type (H4-specific) HATs. As mentioned above, c-Myc can also recruit an H3S10-specific kinase, Pim1, which contributes to c-Myc-induced transcription and transformation [22 • ].…”