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

Mark Stoneley1, Robert F Harvey1, Thomas E Mulroney1

  • 1MRC Toxicology Unit, University of Cambridge, Tennis Court Road, Cambridge CB2 1QR, UK.

Molecular Cell
|February 18, 2022
PubMed

Insights

The ASC-1 complex (ASCC) disassembles stalled ribosomes, but UV- and 4NQO-induced stalled ribosomes are resistant. This resistance prolongs cell-cycle arrest, impacting the stress response.

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Biochemistry

Background:

  • Ribosome-associated quality control is crucial for cellular health.
  • The ASC-1 complex (ASCC) is known to disassemble stalled ribosomes.
  • Understanding differential ribosome stalling is key to cellular stress responses.

Purpose of the Study:

  • To investigate the differential resolution of stalled ribosomes by the ASCC.
  • To determine the impact of ASCC-refractory stalled ribosomes on cellular processes.
  • To elucidate the role of ribosome stalling in cell-cycle regulation and stress response.

Main Methods:

  • Utilized human cell lines to study ribosome stalling.
  • Employed translation elongation inhibitors and mRNA modifications (methylation).
  • Induced DNA damage using UV light and 4-nitroquinoline 1-oxide (4NQO).
  • Investigated ASCC recruitment and activity.
  • Analyzed cell-cycle arrest via ZAK-p38MAPK signaling.

Main Results:

  • Identified two distinct classes of stalled ribosomes based on ASCC sensitivity.
  • Ribosomes stalled by inhibitors or methylated mRNA are rapidly resolved by ASCC.
  • UV- and 4NQO-induced stalled ribosomes are refractory to ASCC-mediated resolution.
  • Unresolved stalled ribosomes persist in cells.
  • Ribosome stalling activates cell-cycle arrest, prolonged by ASCC-refractory stalls.

Conclusions:

  • The sensitivity of stalled ribosomes to the ASCC dictates their resolution kinetics.
  • ASCC-refractory stalled ribosomes contribute to prolonged cell-cycle delay.
  • Differential ribosome stalling resolution influences the adaptive cellular stress response.
Keywords:
ASC-1 complexRNA damageRNA-binding proteincell-cycle arrestribosome stallingribosome-associated quality controlultraviolet light

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