Mitotic checkpoint gene expression is tuned by codon usage bias

EMBO J. 2022 Aug 1;41(15):e107896. doi: 10.15252/embj.2021107896. Epub 2022 Jul 11.

Abstract

The mitotic checkpoint (also called spindle assembly checkpoint, SAC) is a signaling pathway that safeguards proper chromosome segregation. Correct functioning of the SAC depends on adequate protein concentrations and appropriate stoichiometries between SAC proteins. Yet very little is known about the regulation of SAC gene expression. Here, we show in the fission yeast Schizosaccharomyces pombe that a combination of short mRNA half-lives and long protein half-lives supports stable SAC protein levels. For the SAC genes mad2+ and mad3+ , their short mRNA half-lives are caused, in part, by a high frequency of nonoptimal codons. In contrast, mad1+ mRNA has a short half-life despite a higher frequency of optimal codons, and despite the lack of known RNA-destabilizing motifs. Hence, different SAC genes employ different strategies of expression. We further show that Mad1 homodimers form co-translationally, which may necessitate a certain codon usage pattern. Taken together, we propose that the codon usage of SAC genes is fine-tuned to ensure proper SAC function. Our work shines light on gene expression features that promote spindle assembly checkpoint function and suggests that synonymous mutations may weaken the checkpoint.

Keywords: co-translational assembly; gene expression noise; mRNA decay; mitosis; spindle assembly checkpoint.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Cell Cycle Proteins / genetics
  • Cell Cycle Proteins / metabolism
  • Codon Usage
  • Gene Expression
  • Kinetochores / metabolism
  • M Phase Cell Cycle Checkpoints / genetics
  • Mad2 Proteins / metabolism
  • RNA, Messenger / metabolism
  • Schizosaccharomyces pombe Proteins* / genetics
  • Schizosaccharomyces pombe Proteins* / metabolism
  • Schizosaccharomyces* / genetics
  • Schizosaccharomyces* / metabolism
  • Spindle Apparatus / genetics
  • Spindle Apparatus / metabolism

Substances

  • Cell Cycle Proteins
  • Mad2 Proteins
  • RNA, Messenger
  • Schizosaccharomyces pombe Proteins
  • mad3 protein, S pombe