Transcription activation by RNA polymerase II is a complicated process driven by combined, precisely coordinated action of a wide array of coactivator complexes, which carry out chromatin-directed activities and nucleate the assembly of the preinitiation complex on the promoter. Using various techniques, we have shown the existence of a stable coactivator supercomplex consisting of the chromatin-remodeling factor Brahma (SWI/SNF) and the transcription initiation factor TFIID, named BTFly (Brahma and TFIID in one assembly). The coupling of Brahma and TFIID is mediated by the SAYP factor, whose evolutionarily conserved activation domain SAY can directly bind to both BAP170 subunit of Brahma and TAF5 subunit of TFIID. The integrity of BTFly is crucial for its ability to activate transcription. BTFly is distributed genome-wide and appears to be a means of effective transcription activation.coactivators ͉ protein complex A ctivation of transcription by eukaryotic RNA polymerase II (Pol II) requires different groups of coactivators (for reviews, see refs. 1 and 2). The primary function of coactivators is to remodel and modify the chromatin template. Thus, chromatin remodelers of the Brahma (SWI/SNF-related) family play a genome-wide role in activation of Pol II-transcribed genes (3, 4). One more function of coactivators is to further recruit general transcription factors (GTFs) to form the Pol II preinitiation complex. The TFIID coactivator performs this function for most of Pol II-dependent genes (5, 6).Different coactivators recruited to the promoter assist each other and interact in a highly organized gene-specific manner (for a review, see ref. 7). However, this important regulatory step is still poorly understood. The best studied model is that of successive one-by-one recruitment of coactivators, which, in particular, is confirmed by the fact that the recruitment of chromatin-remodeling complexes is usually a prerequisite for the efficient recruitment of GTFs to the promoter (8, 9). The opposite model proposes one-time recruitment of preexisting supercomplex of several coactivators (10-12), although the composition of such supercomplexes described to date appears to be either ambiguous or incomplete.We have described the coactivator SAYP in Drosophila (13). SAYP is present at numerous sites on polytene chromosomes and colocalizes with Pol II in transcriptionally active euchromatin. SAYP homologs in various metazoans have an evolutionarily conserved core containing the SAY domain, which is involved in transcription activation, and 2 PHD fingers (13). Recently, SAYP was found to be associated with the chromatinremodeling Brahma complex of the PBAP subfamily (14). Here, we show that SAYP interacts both with Brahma and with TFIID, assembling them into a stable supercomplex named BTFly (Brahma and TFIID in one assembly). The presence of all BTFly components is crucial for its function in transcription activation. An important fact is that highly purified BTFly contains the full set of TFIID and Brahma subunits and, t...
The PBAF subtype of the mammalian chromatin remodeling SWI/SNF complex has wide and diverse functions in transcription regulation and development, being both transcription activator and repressor. However, a mechanism accounting for such functional diversity remains unclear. Human PHF10/BAF45a subunit of the PBAF complex plays an important role in brain development but has not been studied sufficiently. We have shown that the PHF10 gene encodes 2 types of evolutionarily conserved, ubiquitously expressed isoforms that are incorporated into the PBAF complex in a mutually exclusive manner. One isoform contains C-terminal tandem PHD fingers, which in the other isoform are replaced by the consensus sequence for phosphorylation-dependent SUMO 1 conjugation (PDSM). PBAF complexes containing different PHF10 isoforms can bind to the promoters of the same genes but produce different effects on the recruitment of Pol II to the promoter and on the level of gene transcription. In addition, it is only the PBAF with PHD-containing isoform that activates proliferation. Our study demonstrates the existence of functionally different PBAF complexes in mammalian cell. It also provides an insight into the molecular structure and role of human PHF10/BAF45a and characterizes it as an essential PBAF subunit.
The PBAF chromatin-remodeling complexes are multi-protein machines, regulating expression of genes involved in proliferation and differentiation. PHF10 is a subunit of the PBAF essential for its association with chromatin. Mammalian PHF10 is expressed as four ubiquitous isoforms, which are alternatively incorporated in the complex and differ by their influence on transcription of target genes. PHF10 have different domain structure and two of them (PHF10-S isoforms) lack C-terminal PHD domains, which enables their phosphorylation by CK-1. Here we have found that PBAF subunits have low turnover rate, except for PHF10 which has much lower half-life, and is degraded by β-TrCP. The β-TrCP knockdown stabilizes PBAF core subunits - BRG1 and BAF155 and specific subunits - PHF10, BAF200, BAF180 and BRD7. PHF10 isoforms contain two non-canonical β-TrCP degrons and are degraded by β-TrCP in a phospho-dependent manner. But phosphorylation of PHF10-S degrons by CK-1, contrary to previously described degrons, prevents their degradation. Targeted molecular docking demonstrated that phosphorylated forms of PHF10 bind to β-TrCP with much lower affinity than non-phosphorylated ones, contrary to previously described degrons. This unorthodox mechanism proposes that phosphorylation of β-TrCP degrons by CK-1 could not only degrade a set of proteins, but also stabilize a different set of targets.
SAYP is a dual-function transcription coactivator of RNA polymerase II. It is a metazoan-specific factor with regulated expression that is apparently involved in signaling pathways controlling normal development. In Drosophila, SAYP is maternally loaded into the embryo, participates in cell cycle synchronization in early syncytial embryos, and is indispensible for early embryogenesis. SAYP is abundant in many embryonic tissues and imaginal discs in larvae and is crucial for oogenesis in adults. PHF10 is a mammalian homologue of SAYP whose expression is confined to certain tissues in adults. The molecular mechanism of the SAYP function is related to the conserved domain SAY, which assembles a nuclear supercomplex BTFly consisting of Brahma and TFIID coactivators. We suggest that nuclear supercomplexes may be important means of gene-specific regulation of transcription during development.
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