SPT6 functions in transcriptional pause/release via PAF1C recruitment

Aoi, Yuki; Shah, Avani; Ganesan, Sheetal; Soliman, Shimaa; Cho, Byoung-Kyu; Goo, Young Ah; Kelleher, Neil L.; Shilatifard, Ali

doi:10.1016/j.molcel.2022.06.037

Cited by 36 publications

(26 citation statements)

References 60 publications

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“…3B). However, most of the differential expression observed in response to PAF1 depletion or iPAF1C treatment was up-regulation, indicating greater prevalence of PAF1's role as a negative regulator of RNA Pol II pause-release, as previously reported (1,34). Treatment with iPAF1C largely phenocopied the transcript abundance changes observed upon auxin-induced PAF1 depletion (Fig.…”

Section: Ipaf1c-driven Transcriptional Changes Resemble Acute Depleti...supporting

confidence: 74%

“…1B). It was recently reported that while PAF1 depletion leads to RNA Pol II release and up-regulation of short genes, transcripts from longer gene bodies are mostly down-regulated, due to decreased RNA Pol II processivity and premature termination ( 15 , 34 ). Our global transcriptomic studies following iPAF1C treatment found that, while a majority of differentially expressed genes were up-regulated, a substantial proportion were also down-regulated, consistent with a dual role for PAF1C in regulating both pause-release and processivity (Fig.…”

Section: Discussionmentioning

confidence: 99%

“…PAF1C both positively and negatively regulates transcriptional elongation (1,(30)(31)(32)(33). We recently demonstrated that PAF1 is recruited by SPT6 to maintain RNA Pol II in a paused state at promoter-proximal regions (34). Depletion of PAF1 results in increased recruitment of the P-TEFb-containing super elongation complex (SEC), which increases RNA Pol II release into gene bodies (30).…”

Section: Introductionmentioning

confidence: 99%

“…However, while PAF1C inhibits the licensing of transcriptional elongation at many loci, it also plays a positive role in the progression of productive transcriptional elongation by enhancing RNA Pol II rate and processivity. Depletion of PAF1 reduces elongation rates, resulting in premature termination and decreased transcript abundance, especially for long genes ( 34 ).…”

Section: Introductionmentioning

confidence: 99%

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Enhancing HIV-1 latency reversal through regulating the elongating RNA Pol II pause-release by a small-molecule disruptor of PAF1C

et al. 2023

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The polymerase-associated factor 1 complex (PAF1C) is a key, post-initiation transcriptional regulator of both promoter-proximal pausing and productive elongation catalyzed by RNA Pol II and is also involved in transcriptional repression of viral gene expression during human immunodeficiency virus–1 (HIV-1) latency. Using a molecular docking–based compound screen in silico and global sequencing–based candidate evaluation in vivo, we identified a first-in-class, small-molecule inhibitor of PAF1C (iPAF1C) that disrupts PAF1 chromatin occupancy and induces global release of promoter-proximal paused RNA Pol II into gene bodies. Transcriptomic analysis revealed that iPAF1C treatment mimics acute PAF1 subunit depletion and impairs RNA Pol II pausing at heat shock–down-regulated genes. Furthermore, iPAF1C enhances the activity of diverse HIV-1 latency reversal agents both in cell line latency models and in primary cells from persons living with HIV-1. In sum, this study demonstrates that efficient disruption of PAF1C by a first-in-class, small-molecule inhibitor may have therapeutic potential for improving current HIV-1 latency reversal strategies.

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Section: Ipaf1c-driven Transcriptional Changes Resemble Acute Depleti...supporting

confidence: 74%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Enhancing HIV-1 latency reversal through regulating the elongating RNA Pol II pause-release by a small-molecule disruptor of PAF1C

et al. 2023

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“…Owing to phosphorylation Pol II at Ser 2 by p-TEFb, PAF1C changes its conformation and functions as a positive elongation factor. Moreover, SPT6 (Suppressor of Ty 6) exerts an important function in releasing Pol II through PAF1C recruitment and NELF removal on the surface of RNA Pol II ( Aoi et al, 2022 ). These series of changes can release the promoter-proximal paused Pol II so that transcription elongation proceeds.…”

Section: The Key Events Of the Transcription Cycle In Eukaryotesmentioning

confidence: 99%

The regulation of transcription elongation in embryonic stem cells

Wang

Fan²,

Wu³

2023

Front. Cell Dev. Biol.

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Transcription elongation is a fundamental molecular process which is accurately regulated to ensure proper gene expression in cellular activities whereas its malfunction is associated with impaired cellular functions. Embryonic stem cells (ESCs) have significant value in regenerative medicine due to their self-renewal ability and their potential to differentiate to almost all types of cells. Therefore, dissection of the exact regulatory mechanism of transcription elongation in ESCs is crucial for both basic research and their clinical applications. In this review, we discuss the current understanding on the regulatory mechanisms of transcription elongation mediated by transcription factors and epigenetic modifications in ESCs.

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