scholarly journals The exon-junction complex helicase eIF4A3 controls cell fate via coordinated regulation of ribosome biogenesis and translational output

2021 ◽  
Vol 7 (32) ◽  
pp. eabf7561
Author(s):  
Dimitris C. Kanellis ◽  
Jaime A. Espinoza ◽  
Asimina Zisi ◽  
Elpidoforos Sakkas ◽  
Jirina Bartkova ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Fate ◽  
Ribosome Biogenesis ◽  
Small Subunit ◽  
Initiation Factor ◽  
Exon Junction Complex ◽  
Cell Cycle Regulators ◽  
Nonsense Mediated Decay ◽  
Exon Junction ◽  
Cancer Pathogenesis

Eukaryotic initiation factor 4A-III (eIF4A3), a core helicase component of the exon junction complex, is essential for splicing, mRNA trafficking, and nonsense-mediated decay processes emerging as targets in cancer therapy. Here, we unravel eIF4A3’s tumor-promoting function by demonstrating its role in ribosome biogenesis (RiBi) and p53 (de)regulation. Mechanistically, eIF4A3 resides in nucleoli within the small subunit processome and regulates rRNA processing via R-loop clearance. EIF4A3 depletion induces cell cycle arrest through impaired RiBi checkpoint–mediated p53 induction and reprogrammed translation of cell cycle regulators. Multilevel omics analysis following eIF4A3 depletion pinpoints pathways of cell death regulation and translation of alternative mouse double minute homolog 2 (MDM2) transcript isoforms that control p53. EIF4A3 expression and subnuclear localization among clinical cancer specimens correlate with the RiBi status rendering eIF4A3 an exploitable vulnerability in high-RiBi tumors. We propose a concept of eIF4A3’s unexpected role in RiBi, with implications for cancer pathogenesis and treatment.

scholarly journals The Small Subunit Processome Is Required for Cell Cycle Progression at G1

2004 ◽  
Vol 15 (11) ◽  
pp. 5038-5046 ◽  
Author(s):  
Kara A. Bernstein ◽  
Susan J. Baserga
Keyword(s):  
Cell Cycle ◽  
Ribosome Biogenesis ◽  
Cell Cycle Progression ◽  
Small Subunit ◽  
Cellular Growth ◽  
Yeast Cells ◽  
G1 Phase ◽  
Relay Cell ◽  
Ssu Processome ◽  
Nucleolar Rna

Without ribosome biogenesis, translation of mRNA into protein ceases and cellular growth stops. We asked whether ribosome biogenesis is cell cycle regulated in the yeasts Saccharomyces cerevisiae and Schizosaccharomyces pombe, and we determined that it is not regulated in the same manner as in metazoan cells. We therefore turned our attention to cellular sensors that relay cell size information via ribosome biogenesis. Our results indicate that the small subunit (SSU) processome, a complex consisting of 40 proteins and the U3 small nucleolar RNA necessary for ribosome biogenesis, is not mitotically regulated. Furthermore, Nan1/Utp17, an SSU processome protein, does not provide a link between ribosome biogenesis and cell growth. However, when individual SSU processome proteins are depleted, cells arrest in the G1 phase of the cell cycle. This arrest was further supported by the lack of staining for proteins expressed in post-G1. Similarly, synchronized cells depleted of SSU processome proteins did not enter G2. This suggests that when ribosomes are no longer made, the cells stall in the G1. Therefore, yeast cells must grow to a critical size, which is dependent upon having a sufficient number of ribosomes during the G1 phase of the cell cycle, before cell division can occur.

scholarly journals Identification of antiviral roles for the exon–junction complex and nonsense-mediated decay in flaviviral infection

2019 ◽  
Vol 4 (6) ◽  
pp. 985-995 ◽  
Author(s):  
Minghua Li ◽  
Jeffrey R. Johnson ◽  
Billy Truong ◽  
Grace Kim ◽  
Nathan Weinbren ◽  
...  
Keyword(s):  
Exon Junction Complex ◽  
Nonsense Mediated Decay ◽  
Exon Junction

eIF4AIII binds spliced mRNA in the exon junction complex and is essential for nonsense-mediated decay

2004 ◽  
Vol 11 (4) ◽  
pp. 346-351 ◽  
Author(s):  
Toshiharu Shibuya ◽  
Thomas Ø Tange ◽  
Nahum Sonenberg ◽  
Melissa J Moore
Keyword(s):  
Exon Junction Complex ◽  
Nonsense Mediated Decay ◽  
Exon Junction

scholarly journals Co-ordination of cell cycle and differentiation in the developing nervous system

2012 ◽  
Vol 444 (3) ◽  
pp. 375-382 ◽  
Author(s):  
Christopher Hindley ◽  
Anna Philpott
Keyword(s):  
Cell Cycle ◽  
Nervous System ◽  
Embryonic Development ◽  
Cell Fate ◽  
Cell Cycle Progression ◽  
Control Cell ◽  
Cell Cycle Regulators ◽  
Cyclin Dependent Kinases ◽  
Proliferation And Differentiation ◽  
Developing Nervous System

During embryonic development, cells must divide to produce appropriate numbers, but later must exit the cell cycle to allow differentiation. How these processes of proliferation and differentiation are co-ordinated during embryonic development has been poorly understood until recently. However, a number of studies have now given an insight into how the cell cycle machinery, including cyclins, CDKs (cyclin-dependent kinases), CDK inhibitors and other cell cycle regulators directly influence mechanisms that control cell fate and differentiation. Conversely, examples are emerging of transcriptional regulators that are better known for their role in driving the differentiated phenotype, which also play complementary roles in controlling cell cycle progression. The present review will summarise our current understanding of the mechanisms co-ordinating the cell cycle and differentiation in the developing nervous system, where these links have been, perhaps, most extensively studied.

scholarly journals Swm1/Apc13 Is an Evolutionarily Conserved Subunit of the Anaphase-Promoting Complex Stabilizing the Association of Cdc16 and Cdc27

2004 ◽  
Vol 24 (8) ◽  
pp. 3562-3576 ◽  
Author(s):  
Martin Schwickart ◽  
Jan Havlis ◽  
Bianca Habermann ◽  
Aliona Bogdanova ◽  
Alain Camasses ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Budding Yeast ◽  
Small Subunit ◽  
Cell Cycle Regulators ◽  
Anaphase Promoting Complex ◽  
Ubiquitin Ligase Activity ◽  
Evolutionarily Conserved ◽  
Stable Association

ABSTRACT The anaphase-promoting complex (APC/C) is a large ubiquitin-protein ligase which controls progression through anaphase by triggering the degradation of cell cycle regulators such as securin and B-type cyclins. The APC/C is an unusually complex ligase containing at least 10 different, evolutionarily conserved components. In contrast to APC/C's role in cell cycle regulation little is known about the functions of individual subunits and how they might interact with each other. Here, we have analyzed Swm1/Apc13, a small subunit recently identified in the budding yeast complex. Database searches revealed proteins related to Swm1/Apc13 in various organisms including humans. Both the human and the fission yeast homologues are associated with APC/C subunits, and they complement the phenotype of an SWM1 deletion mutant of budding yeast. Swm1/Apc13 promotes the stable association with the APC/C of the essential subunits Cdc16 and Cdc27. Accordingly, Swm1/Apc13 is required for ubiquitin ligase activity in vitro and for the timely execution of APC/C-dependent cell cycle events in vivo.

scholarly journals CASC3 promotes transcriptome-wide activation of nonsense-mediated decay by the exon junction complex

2020 ◽  
Vol 48 (15) ◽  
pp. 8626-8644 ◽  
Author(s):  
Jennifer V Gerbracht ◽  
Volker Boehm ◽  
Thiago Britto-Borges ◽  
Sebastian Kallabis ◽  
Janica L Wiederstein ◽  
...  
Keyword(s):  
Exon Junction Complex ◽  
Core Component ◽  
Mrna Isoforms ◽  
Nonsense Mediated Decay ◽  
Exon Junction ◽  
Endonucleolytic Cleavage ◽  
Core Proteins ◽  
Messenger Ribonucleoprotein ◽  
Cytoplasmic Processes

Abstract The exon junction complex (EJC) is an essential constituent and regulator of spliced messenger ribonucleoprotein particles (mRNPs) in metazoans. As a core component of the EJC, CASC3 was described to be pivotal for EJC-dependent nuclear and cytoplasmic processes. However, recent evidence suggests that CASC3 functions differently from other EJC core proteins. Here, we have established human CASC3 knockout cell lines to elucidate the cellular role of CASC3. In the knockout cells, overall EJC composition and EJC-dependent splicing are unchanged. A transcriptome-wide analysis reveals that hundreds of mRNA isoforms targeted by nonsense-mediated decay (NMD) are upregulated. Mechanistically, recruiting CASC3 to reporter mRNAs by direct tethering or via binding to the EJC stimulates mRNA decay and endonucleolytic cleavage at the termination codon. Building on existing EJC-NMD models, we propose that CASC3 equips the EJC with the persisting ability to communicate with the NMD machinery in the cytoplasm. Collectively, our results characterize CASC3 as a peripheral EJC protein that tailors the transcriptome by promoting the degradation of EJC-dependent NMD substrates.

scholarly journals Communication with the Exon-Junction Complex and Activation of Nonsense-Mediated Decay by Human Upf Proteins Occur in the Cytoplasm

2007 ◽  
Vol 27 (5) ◽  
pp. 780-792 ◽  
Author(s):  
Guramrit Singh ◽  
Steffen Jakob ◽  
Mark G. Kleedehn ◽  
Jens Lykke-Andersen
Keyword(s):  
Exon Junction Complex ◽  
Nonsense Mediated Decay ◽  
Exon Junction
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