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The exon-junction c...
The exon-junction complex helicase eIF4A3 controls cell fate via coordinated regulation of ribosome biogenesis and translational output
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- Kanellis, Dimitris C. (author)
- Karolinska Institutet
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- Espinoza, Jaime A. (author)
- Karolinska Institutet
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- Zisi, Asimina (author)
- Karolinska Institutet
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- Sakkas, Elpidoforos (author)
- Stockholms universitet,Institutionen för molekylär biovetenskap, Wenner-Grens institut
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- Bartkova, Jirina (author)
- Karolinska Institutet
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Katsori, Anna-Maria (author)
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Boström, Johan (author)
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Dyrskjøt, Lars (author)
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Broholm, Helle (author)
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- Altun, Mikael (author)
- Karolinska Institutet
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- Elsässer, Simon J. (author)
- Karolinska Institutet
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- Lindström, Mikael S. (author)
- Karolinska Institutet
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- Bartek, Jiri (author)
- Karolinska Institutet
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(creator_code:org_t)
- American Association for the Advancement of Science (AAAS), 2021
- 2021
- English.
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In: Science Advances. - : American Association for the Advancement of Science (AAAS). - 2375-2548. ; 7:32
- Related links:
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https://doi.org/10.1...
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https://www.science....
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https://urn.kb.se/re...
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Abstract
Subject headings
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- 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.
Subject headings
- NATURVETENSKAP -- Biologi -- Biokemi och molekylärbiologi (hsv//swe)
- NATURAL SCIENCES -- Biological Sciences -- Biochemistry and Molecular Biology (hsv//eng)
Publication and Content Type
- ref (subject category)
- art (subject category)
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- By the author/editor
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Kanellis, Dimitr ...
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Espinoza, Jaime ...
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Zisi, Asimina
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Sakkas, Elpidofo ...
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Bartkova, Jirina
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Katsori, Anna-Ma ...
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show more...
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Boström, Johan
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Dyrskjøt, Lars
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Broholm, Helle
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Altun, Mikael
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Elsässer, Simon ...
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Lindström, Mikae ...
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Bartek, Jiri
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- About the subject
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- NATURAL SCIENCES
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NATURAL SCIENCES
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and Biological Scien ...
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and Biochemistry and ...
- Articles in the publication
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Science Advances
- By the university
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Stockholm University
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Karolinska Institutet