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TTC33-associated network (TAN) is a novel vertebrate-specific complex formed by TTC33, WDR61 and PHF5A

ABSTRACT: TTC33 is an uncharacterized vertebrate-specific structural protein composed of tetratricopeptide repeat motifs. TTC3 forms a trimeric complex with WDR61 and chromatin binding PHF5A, coined TAN for TTC33-associated network. The TAN complex is associated with structural protein CCDC97, SF3A/B U2 splicing factor sub-complex, PP2A phosphatase and UNG DNA glycosylase.

ORGANISM(S): Homo sapiens

PROVIDER: GSE234217 | GEO | 2024/11/05

REPOSITORIES: GEO

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TTC33-associated network (TAN) is a novel vertebrate-specific complex formed by TTC33, WDR61 and PHF5A

Project description:TTC33-associated network (TAN) is a novel vertebrate-specific complex formed by TTC33, WDR61 and PHF5A

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Splicing Modulators Act at the Branch Point Adenosine Binding Pocket Defined by the PHF5A-SF3b Complex

Project description:Developing small-molecule splicing modulators represents a promising therapeutic approach for various diseases. Natural products such as pladienolide, herboxidiene, and spliceostatin have been identified as potent splicing modulators that target SF3B1 in the SF3b subcomplex. Using integrated chemogenomic, structural and biochemical approaches, we show that PHF5A, another core component of the SF3b complex, is also targeted by these compounds. Mutations in PHF5A-Y36, SF3B1-K1071, SF3B1-R1074, and SF3B1-V1078 confer resistance to these modulators, suggesting a common site of interaction. Whole-transcriptome RNA-seq analysis reveals that PHF5A-Y36C has minimal effect on basal splicing but alters the action of splicing modulators from inducing intron-retention to exon-skipping. Relative intron strength to splicing inhibition correlates with the differential in GC content between adjacent introns and exons, leading to this differential global splicing pattern. We determine the crystal structure of human PHF5A and find that Y36 is located on the surface in a region of high sequence conservation. Structural analysis of the cryo-EM spliceosome Bact complex shows that these mutations cluster in a well-defined pocket surrounding the branch point adenosine suggesting a possible competitive mode of action for these splicing modulators, which interact with the aromatic side-chain of PHF5A-Y36. Collectively, we propose that PHF5A-SF3B1 forms a central node for binding to these small-molecule splicing modulators, offering insights to modulate splicing.

2017-05-25 | GSE96917 | GEO

Nascent transript profiling upon in mouse embryonic stem cells under control conditions or Phf5a knockdown

Project description:Phf5a regulates transcription elongation in mouse embryonic stem cells (ESCs), through regulation of the Paf1 complex. In this study we assayed nascent RNA profiling using global run-on sequncing in mouse ESCs under conditions of self-renewal, differentiation and Phf5a knockdown. These results revealed that genes positively regulated by Paf1 in ESCs exibit RNA elongation pausing on their promoters. We used conditions of self-renewal, differentiation, Phf5a knockdown and Paf1 knockdown to monitor nascent transcript expression changes during Phf5a depletion using global run-on RNA sequencing (GRO-seq). These results revealed that Phf5a through the control of Paf1 complex regulates pause release and elongation of pluripoency-associated genes in embryonic stem cells.

2016-08-31 | GSE73441 | GEO

Overlapping roles of spliceosomal components SF3B1 and PHF5A in rice splicing regulation

Project description:The SF3B complex, a multiprotein component of the U2 snRNP of the spliceosome, mediates branch point selection and facilitates spliceosome assembly and activation. Several splicing modulators bind the SF3B1 and PHF5A subunits of the SF3B complex and globally inhibit splicing. Engineered mutant variants of SF3B1 and PHF5A conferred tolerance to splicing inhibitors with only minor effects on gene expression and AS.

2021-04-11 | GSE153234 | GEO

Gene expression profiling using RNA-sequencing in mouse embryonic stem cells under control conditions or Phf5a knockdown

Project description:Phf5a regulates transcription elongation in mouse embryonic stem cells (ESCs), through regulation of the Paf1 complex. In this study we assayed gene expression profiling using RNA-sequncing in mouse ESCs under conditions of self-renewal, Phf5a knockdown and Paf1 knockdown. These results revealed that Phf5a and Paf1 regulate similar gene expression signatures in mouse ESCs.

2016-08-31 | GSE86248 | GEO

Characterization of Paf1 complex occupancy in mouse embryonic stem cells under control conditions or Phf5a knockdown

Project description:Phf5a regulates transcription elongation in mouse embryonic stem cells (ESCs), through regulation of the Paf1 complex. In this study we assayed for genome-wide localization of Paf1, Leo1 and Cdc73 subunits of the Paf1 complex in mouse ESCs under conditions of shControl and shPhf5a knockdown. These results revealed that downregualtion of Phf5a results in the significant decrease of Paf1 complex binding to its targets in ESCs.

2016-08-31 | GSE73445 | GEO

Characterization of Paf1 complex occupancy in mouse myoblasts and myotubes under control conditions or Phf5a knockdown

Project description:Phf5a regulates occupancy of Paf1 complex in mouse myotubes. In this study we assayed for genome-wide localization of Leo1 subunit of the Paf1 complex in mouse myoblasts or myotubes under conditions of shControl or shPhf5a knockdown. These results revealed that downregualtion of Phf5a results in significant decrease of Leo1 binding to its targets in myotubes.

2016-08-31 | GSE86249 | GEO

Transcriptome-wide identification of transcripts regulated by PHF5A in colorectal cancer cells

Project description:Dysregulated alternative splicing (AS) plays critical roles in driving cancer progression, and the underlying mechanisms remain largely unknown. Here we demonstrated that PHF5A, a component of U2 snRNPs, was frequently upregulated in colorectal cancer (CRC) samples and associated with poor prognosis. PHF5A promoted proliferation and metastasis of CRC cells in vitro and in vivo. Transcriptomic analysis identified PHF5A-regulated AS targets and pathways. Particularly, PHF5A induced TEAD2 exon 2 inclusion to activate YAP signaling, and interference of TEAD2-L partially reversed the PHF5A-mediated tumor progression. Pharmacological inhibition of PHF5A using pladienolide B had potent antitumor activity. Collectively, these data revealed the oncogenic role of PHF5A in CRC through regulating AS, and established PHF5A as potential therapeutic target.

2021-07-16 | GSE180042 | GEO

PHF5A coordinates p300 for epigenetic regulation of lipogenesis to promote hepatocellular carcinoma progression

Project description:PHD-finger protein 5A (PHF5A) is a component of U2snRNP, which plays a critical role in mRNA splicing for recognizing the branch site. However, whether it also plays other functions independent of RNA splicing remains elusive. Here, we find that expression levels of PHF5A are significantly upregulated in hepatocellular carcinoma (HCC). Down-regulation of PHF5A restrains liver cancer cell proliferation in vitro and in vivo. RNA-sequencing analysis reveals that fatty-acid biosynthetic enzymes are major downstream targets of PHF5A in HCC. Through metabolomics analysis, we find that inhibition of PHF5A reduces free fatty acid and phospholipid synthesis, further suppressing plasma membrane function. Mechanistically, PHF5A acts as a transcription co-factor of the p300 acetyltransferase for the H3K27 acetylation (Ac) and promotes H3K27Ac-dependent lipogenic genes expression. Our findings demonstrated a surprising splicing-independent role of PHF5A in transcriptional regulation of lipid metabolism for HCC progression and provided a new strategy for HCC therapy by blocking the interaction of PHF5A and p300.

2021-10-01 | GSE167023 | GEO

Characterization of histone modifications in mouse embryonic stem cells under control conditions or Phf5a knockdown

Project description:Phf5a regulates transcription elongation in mouse embryonic stem cells (ESCs), through regulation of the Paf1 complex. In this study we assayed for genome-wide localization of H3K4me3, H3K79me2 and H3K36me3 in mouse ESCs under conditions of shControl and shPhf5a knockdown. These results revealed that downregualtion of Phf5a results in the decrease of the elongation marks H3K79me2 and H3K36me3 from the gene bodies of pluripotency genes in ESC, wherease the promoter-associated mark H3K4me3 remains unaffected.

2016-08-31 | GSE73442 | GEO

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