Unresolved stalled ribosome complexes restrict cell-cycle progression after genotoxic stress.

Autor:	Stoneley M; MRC Toxicology Unit, University of Cambridge, Tennis Court Road, Cambridge CB2 1QR, UK. Electronic address: ms2510@mrc-tox.cam.ac.uk., Harvey RF; MRC Toxicology Unit, University of Cambridge, Tennis Court Road, Cambridge CB2 1QR, UK., Mulroney TE; MRC Toxicology Unit, University of Cambridge, Tennis Court Road, Cambridge CB2 1QR, UK., Mordue R; MRC Toxicology Unit, University of Cambridge, Tennis Court Road, Cambridge CB2 1QR, UK., Jukes-Jones R; MRC Toxicology Unit, University of Cambridge, Tennis Court Road, Cambridge CB2 1QR, UK., Cain K; MRC Toxicology Unit, University of Cambridge, Tennis Court Road, Cambridge CB2 1QR, UK., Lilley KS; Cambridge Centre for Proteomics, Cambridge Systems Biology Centre, Department of Biochemistry, University of Cambridge, Cambridge CB2 1QR, UK., Sawarkar R; MRC Toxicology Unit, University of Cambridge, Tennis Court Road, Cambridge CB2 1QR, UK., Willis AE; MRC Toxicology Unit, University of Cambridge, Tennis Court Road, Cambridge CB2 1QR, UK. Electronic address: aew80@mrc-tox.cam.ac.uk.
Jazyk:	angličtina
Zdroj:	Molecular cell [Mol Cell] 2022 Apr 21; Vol. 82 (8), pp. 1557-1572.e7. Date of Electronic Publication: 2022 Feb 17.
DOI:	10.1016/j.molcel.2022.01.019
Abstrakt:	During the translation surveillance mechanism known as ribosome-associated quality control, the ASC-1 complex (ASCC) disassembles ribosomes stalled on the mRNA. Here, we show that there are two distinct classes of stalled ribosome. Ribosomes stalled by translation elongation inhibitors or methylated mRNA are short lived in human cells because they are split by the ASCC. In contrast, although ultraviolet light and 4-nitroquinoline 1-oxide induce ribosome stalling by damaging mRNA, and the ASCC is recruited to these stalled ribosomes, we found that they are refractory to the ASCC. Consequently, unresolved UV- and 4NQO-stalled ribosomes persist in human cells. We show that ribosome stalling activates cell-cycle arrest, partly through ZAK-p38 MAPK signaling, and that this cell-cycle delay is prolonged when the ASCC cannot resolve stalled ribosomes. Thus, we propose that the sensitivity of stalled ribosomes to the ASCC influences the kinetics of stall resolution, which in turn controls the adaptive stress response. Competing Interests: Declaration of interests A.E.W. is a member of the Molecular Cell advisory board. (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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