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Phenotypic Screens Identify SCAF1 as Critical Activator of RNAPII Elongation and Global Transcription

ABSTRACT: Phenotypic Screens Identify SCAF1 as Critical Activator of RNAPII Elongation and Global Transcription

PROVIDER: PRJNA1140212 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR29995642_1.fastq.gz	Fastqsanger.gz
	SRR29995642_2.fastq.gz	Fastqsanger.gz
	SRR29995643_1.fastq.gz	Fastqsanger.gz
	SRR29995643_2.fastq.gz	Fastqsanger.gz
	SRR29995644_1.fastq.gz	Fastqsanger.gz

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Phenotypic Screens Identify SCAF1 as Critical Activator of RNAPII Elongation and Global Transcription [4sU-seq]

Project description:Transcripts produced by RNA polymerase II (RNAPII) are fundamental for cellular responses to environmental changes. It is therefore no surprise that there exist multiple avenues for the regulation of this process. To explore the regulation mediated by RNAPII-interacting proteins, we used an siRNA-based screen to systematically evaluate their influence on RNA synthesis. We identified several proteins that strongly affected RNAPII activity. We evaluated one of the top hits, SCAF1, using an auxin-inducible degradation system and sequencing approaches. In agreement with our screen results, acute depletion of SCAF1 decreased RNA synthesis, and showed an increase of Serine-2 phosphorylated-RNAPII (pS2-RNAPII). We found that the accumulation of pS2-RNAPII within the gene body occurred at GC-rich regions and was indicative of stalled RNAPII complexes. The accumulation of stalled RNAPII complexes was accompanied by reduced recruitment of initiating RNAPII, explaining the observed global decrease in transcriptional output. Furthermore, upon SCAF1 depletion, RNAPII complexes showed increased association with components of the proteasomal-degradation machinery. We concluded that in cells lacking SCAF1, RNAPII undergoes a rather interrupted passage, resulting in intervention by the proteasomal-degradation machinery to clear stalled RNAPII. While cells survive the compromised transcription caused by absence of SCAF1, further inhibition of proteasomal-degradation machinery, is synthetically lethal.

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Phenotypic Screens Identify SCAF1 as Critical Activator of RNAPII Elongation and Global Transcription [ChIP-seq]

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Phenotypic Screens Identify SCAF1 as Critical Activator of RNAPII Elongation and Global Transcription [ChIP-seq]

Project description:Phenotypic Screens Identify SCAF1 as Critical Activator of RNAPII Elongation and Global Transcription [ChIP-seq]

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Phenotypic Screens Identify SCAF1 as Critical Activator of RNAPII Elongation and Global Transcription [CUT&RUN]

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Phenotypic Screens Identify SCAF1 as Critical Activator of RNAPII Elongation and Global Transcription [4sU-seq]

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Phenotypic Screens Identify SCAF1 as Critical Activator of RNAPII Elongation and Global Transcription

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RNA Polymerase II interactome in presence or absence of SCAF1 in U2OS-SCAF1-AID cells

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Project description:Functionally characterizing the genetic alterations that drive pancreatic cancer progression is a prerequisite for precision pedicine. Here, we developed a somatic CRISPR/Cas9 mutagenesis screen to assess the transforming potential of 125 recurrently mutated ‘long-tail’ pancreatic cancer genes, which revealed USP15 and SCAF1 as novel and potent pancreatic ductal adenocarcinoma PDAC tumor suppressors, with USP15 functioning in a haplo-insufficient manner. Mechanistically, we found that loss of USP15 leads to reduced inflammatory responses associated with TNFa, TGF-b and IL6 signaling and sensitizes pancreatic cancer cells to PARP inhibition and Gemcitabine. Similarly, genetic ablation of SCAF1 reduced inflammatory responses linked to TNFa, TGF-b and mTOR signaling and increased sensitivity to PARP inhibition. Furthermore, we identified that loss of SCAF1 resulted in the formation of a truncated inactive USP15 isoform at the expense of full length USP15, functionally coupling SCAF1 and USP15. Notably, USP15 and SCAF1 mutations or copy number losses are observed in 31% of PDAC patients. Together, our results demonstrate the utility of in vivo CRISPR screens to integrate human cancer genomics with mouse modeling for selective discovery of novel cancer driver genes such as USP15 and SCAF1 with potential prognostic and therapeutic implications.

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