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Nuclear actin regulates inducible transcription by enhancing RNA polymerase II clustering.

ABSTRACT: Gene expression in response to stimuli underlies many fundamental processes. However, how transcription is regulated under these scenarios is largely unknown. Here, we find a previously unknown role of nuclear actin in transcriptional regulation. The RNA-seq data reveal that nuclear actin is required for the serum-induced transcriptional program. Using super-resolution imaging, we found a remarkable enhancement of RNA polymerase II (Pol II) clustering upon serum stimulation, and this enhancement requires nuclear actin. Pol II clusters colocalized with the serum-response genes and nuclear actin filaments upon serum stimulation. Furthermore, N-WASP is required for serum-enhanced Pol II clustering. N-WASP phase-separated with Pol II and nuclear actin. In addition to serum stimulation, nuclear actin also enhanced Pol II clustering upon interferon-γ treatment. Together, our work unveils that nuclear actin promotes the formation of transcription factory on inducible genes, acting as a general mechanism underlying the rapid response to environmental cues.

SUBMITTER: Wei M

PROVIDER: S-EPMC7159918 | biostudies-literature | 2020 Apr

REPOSITORIES: biostudies-literature

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Nuclear actin regulates inducible transcription by enhancing RNA polymerase II clustering.

Wei Mian M Fan Xiaoying X Ding Miao M Li Ruifeng R Shao Shipeng S Hou Yingping Y Meng Shaoshuai S Tang Fuchou F Li Cheng C Sun Yujie Y

Science advances 20200415 16

Gene expression in response to stimuli underlies many fundamental processes. However, how transcription is regulated under these scenarios is largely unknown. Here, we find a previously unknown role of nuclear actin in transcriptional regulation. The RNA-seq data reveal that nuclear actin is required for the serum-induced transcriptional program. Using super-resolution imaging, we found a remarkable enhancement of RNA polymerase II (Pol II) clustering upon serum stimulation, and this enhancement ...[more]

PMID: 32494599

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Project description:Ribonucleoside analogues have potential utility as anti-viral, -parasitic, -bacterial and -cancer agents. However, their clinical applications have been limited by off target effects. Development of antiviral ribonucleosides for treatment of hepatitis C virus (HCV) infection has been hampered by appearance of toxicity during clinical trials that evaded detection during preclinical studies. It is well established that the human mitochondrial DNA polymerase is an off target for deoxyribonucleoside reverse transcriptase inhibitors. Here we test the hypothesis that triphosphorylated metabolites of therapeutic ribonucleoside analogues are substrates for cellular RNA polymerases. We have used ribonucleoside analogues with activity against HCV as model compounds for therapeutic ribonucleosides. We have included ribonucleoside analogues containing 2'-C-methyl, 4'-methyl and 4'-azido substituents that are non-obligate chain terminators of the HCV RNA polymerase. We show that all of the anti-HCV ribonucleoside analogues are substrates for human mitochondrial RNA polymerase (POLRMT) and eukaryotic core RNA polymerase II (Pol II) in vitro. Unexpectedly, analogues containing 2'-C-methyl, 4'-methyl and 4'-azido substituents were inhibitors of POLRMT and Pol II. Importantly, the proofreading activity of TFIIS was capable of excising these analogues from Pol II transcripts. Evaluation of transcription in cells confirmed sensitivity of POLRMT to antiviral ribonucleosides, while Pol II remained predominantly refractory. We introduce a parameter termed the mitovir (mitochondrial dysfunction caused by antiviral ribonucleoside) score that can be readily obtained during preclinical studies that quantifies the mitochondrial toxicity potential of compounds. We suggest the possibility that patients exhibiting adverse effects during clinical trials may be more susceptible to damage by nucleoside analogs because of defects in mitochondrial or nuclear transcription. The paradigm reported here should facilitate development of ribonucleosides with a lower potential for toxicity.

Dataset Information

Nuclear actin regulates inducible transcription by enhancing RNA polymerase II clustering.

Publications

Nuclear actin regulates inducible transcription by enhancing RNA polymerase II clustering.

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