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ARF alters PAF1 complex integrity to selectively repress oncogenic transcription programs upon p53 loss

ABSTRACT: In this study, we found that the ARF tumor suppressor directly binds the PAF1 subunit to block the assembly of PAF1 complex (PAF1c) and its interaction with RNAPII, thereby dampening PAF1c-dependent transcription in vitro and in cells. Using RNA-seq of control (shNT) and ARF knockdown (shARF) mouse embryonic fibroblasts (MEFs) we first define transcriptome changes upon ARF loss. Through downstream mechanistic analysis we then validate direct ARF-mediated inactivation of PAF1c-dependent RNAPII transcription and their cellular consequences.

ORGANISM(S): Mus musculus

PROVIDER: GSE217766 | GEO | 2024/10/10

REPOSITORIES: GEO

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ARF alters PAF1 complex integrity to selectively repress oncogenic transcription programs upon p53 loss

Project description:In this study, we found that the ARF tumor suppressor directly binds the PAF1 subunit to block the assembly of PAF1 complex (PAF1c) and its interaction with RNAPII, thereby dampening PAF1c-dependent transcription in vitro and in cells. To investigate whether ARF regulates RNAPII and PAF1c occupancy at putative target genes identified through RNA-seq, we performed ChIP-seq (RNAPII, PAF1, and CTR9) in ARF (shARF) vs. control (shNT) knockdown MEFs. Our data show that loss of ARF increases RNAPII, PAF1, and CTR9 occupancy on upregulated genes, consistent with ARF-mediated gene-specific repression. Chromatin immunoprecipitation DNA-sequencing (ChIP-seq) for RNA polymerase subunit RPB3 and PAF1 complex subunits PAF1 and CTR9 in mouse embryonic fibroblasts.

2024-10-10 | GSE217765 | GEO

ARF alters PAF1 complex integrity to selectively repress oncogenic transcription programs upon p53 loss

Project description:ARF alters PAF1 complex integrity to selectively repress oncogenic transcription programs upon p53 loss

| PRJNA900284 | ENA

ARF alters PAF1 complex integrity to selectively repress oncogenic transcription programs upon p53 loss

Project description:ARF alters PAF1 complex integrity to selectively repress oncogenic transcription programs upon p53 loss

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ARF alters PAF1 complex integrity to selectively repress oncogenic transcription programs upon p53 loss

Project description:ARF alters PAF1 complex integrity to selectively repress oncogenic transcription programs upon p53 loss

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Multiple direct and indirect roles of the Paf1 Complex in elongation, splicing, and histone post-translational modifications [RNA-seq]

Project description:Eukaryotes employ a set of conserved transcription elongation factors to modulate the behavior of RNA polymerase II (RNAPII). Disruptions of one such factor, the Paf1 complex (Paf1C), generate subunit-specific phenotypes, including distinct changes to co-transcriptional histone modifications. How individual Paf1C subunits impact transcription and coupled processes remains ambiguous. By comparing conditional depletion and steady-state deletion of Paf1C subunits, we determine direct and indirect contributions of Paf1C to gene expression in Saccharomyces cerevisiae. Through nascent transcript sequencing, RNAPII profiling, and mechanistic modeling of transcription elongation dynamics, we find evidence for unique roles of Paf1C subunits in regulating RNAPII processivity, elongation rate, mRNA stability, transcript splicing, and repression of antisense transcripts. Through genetic suppression, we attribute increased antisense transcription, but not other defects, of a PAF1 mutant to loss of H3 K36 methylation. This work comprehensively analyzes both the immediate and extended roles of Paf1C subunits in transcription elongation and transcript regulation.

2024-05-15 | GSE255362 | GEO

Multiple direct and indirect roles of the Paf1 Complex in elongation, splicing, and histone post-translational modifications [ChIP-seq]

2024-05-15 | GSE255361 | GEO

Multiple direct and indirect roles of the Paf1 Complex in elongation, splicing, and histone post-translational modifications [4tU-seq]

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A CSB-PAF1 axis activates RNA polymerase II from promoter-proximal sites and restores efficient transcription elongation after DNA damage repair

Project description:The coordinated transcription of genes involves RNA polymerase II enzymes (RNAPII), which pull DNA through their active sites. DNA lesions in transcribed strands block RNAPII elongation and induce a strong transcriptional arrest. The transcription-coupled repair (TCR) pathway ensures the efficient removal of transcription-blocking DNA lesions, but this is not sufficient to overcome this arrest and resume transcription. Through proteomics screens, we find that the TCR-specific CSB protein loads the evolutionary conserved PAF1 complex (PAF1C) onto RNAPII in promoter-proximal regions specifically in response to DNA damage. PAF1C is dispensable for TCR-mediated repair,but is essential to resume RNA synthesis after UV irradiation, suggesting an unexpected uncoupling between DNA repair and transcription restart. Moreover, we find that PAF1C promotes RNAPII pause release in promoter-proximal regions and subsequently acts as a processivity factor that stimulates transcription elongation waves throughout genes. Our findings expose the molecular basis for a non-canonical PAF1C-dependent pathway that restores transcription throughout the human genome after genotoxic stress.

2021-02-28 | PXD016198 | Pride

The Paf1 complex broadly impacts the transcriptome of Saccharomyces cerevisiae

Project description:The polymerase associated factor 1 complex (Paf1C) is a multifunctional epigenetic regulator of RNA polymerase II (Pol II) transcription. Paf1C controls gene expression by stimulating the placement of co-transcriptional histone modifications, influencing nucleosome occupancy in coding regions, facilitating transcription termination, and regulating nuclear export of RNAs. In this study, we investigate the extent to which these functions of Paf1C combine to influence the Saccharomyces cerevisiae transcriptome. Using conditions that enrich for unstable transcripts, we show that deletion of PAF1 affects all classes of Pol II-transcribed RNAs including multiple classes of noncoding transcripts. Gene ontology analysis revealed that mRNAs encoding genes involved in iron and phosphate homeostasis were differentially affected by deletion of PAF1. We further investigated these two groups of mRNAs with the goal of identifying overarching mechanisms of up and down-regulation in cells lacking Paf1. Our results indicate that only a subset of the observed changes result from loss of Paf1C-promoted histone modifications. We also found that transcription of the FET4 gene is differentially regulated by Paf1 and an upstream CUT. Together these data highlight the complexity of the epigenetic regulation of Pol II transcription imposed by Paf1C and identify a role for Paf1C in promoting CUT transcription.

2019-06-11 | GSE122704 | GEO

The PAF1 complex promotes 3‘ processing of pervasive transcripts [PRO-Seq]

Project description:The PAF1 complex (PAF1C) functions in multiple transcriptional and co-transcriptional processes. Although many aspects of the requirement for PAF1 in coding gene transcription have been heavily studied, the function of PAF1C at sites of non-coding transcription is poorly understood. eRNAs and PROMPTs are pervasive transcripts transcribed by RNA Polymerase II and rapidly degraded after 3’ endonucleolytic cleavage by the Integrator complex (Integrator). Here we show that PAF1C depletion results in near universal 3’ end processing defects in pervasive transcripts, leading to transcription termination dysregulation. Mechanistically, PAF1C recruits Integrator to chromatin through direct interactions promoting timely cleavage and transcription termination of pervasive transcripts. We also show that PAF1C recruits Integrator to the promoters of coding genes, where PAF1C then dissociates from the Integrator complex upon entry into processive elongation. Our results demonstrate an unexpected function for PAF1C in limiting the length and accumulation of pervasive transcripts, while highlighting a general requirement for PAF1C in Integrator recruitment.

2022-03-15 | GSE163501 | GEO

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