Cell‐Cycle‐Dependent Regulation of Translation: New Interpretations of Old Observations in Light of New Approaches

Abstract

It is a long‐standing view that global translation varies during the cell cycle and is much lower in mitosis than in other cell‐cycle phases. However, the central papers in the literature are not in agreement about the extent of downregulation in mitosis, ranging from a dramatic decrease to only a marginal reduction. Herein, it is argued that the discrepancy derives from technical challenges. Cell‐cycle‐dependent variations are most conveniently studied in synchronized cells, but the synchronization methods by themselves often evoke stress responses that, in turn, affect translation rates. Further, it is argued that previously reported cell‐cycle‐dependent changes in the global translation rate to a large extent reflect responses to the synchronization methods. Recent findings strongly suggest that the global translation rate is not regulated in a cell‐cycle‐dependent manner. Novel techniques allowing a genome‐wide analysis of translational profiles suggest that the extent and importance of selective translational regulation associated with cell‐cycle transitions have been underestimated. Therefore, the main question is which messenger RNAs (mRNAs) are translated, rather than whether the global translation rate is decreased.

Differential translation of mRNA isoforms underlies oncogenic activation of cell cycle kinase Aurora A

“…Given the known cell cycle-dependent expression of AURKA (3), we tested whether differential translational efficiency of AURKA mRNA isoforms might contribute to this regulation. To avoid perturbation of translation provoked by classical cell synchronization methods (61), we used a live-cell fluorescence-based translation rate measurement assay in conjunction with a CDK2 activity sensor (62) for in silico cell cycle synchronization. We developed our assay of ‘Translation Rate Imaging by rate of Protein Stabilization’ (TRIPS) based on a previously introduced reporter system (63) (64).…”

Differential translation of mRNA isoforms underlies oncogenic activation of cell cycle kinase Aurora A

“…Given the known cell cycle-dependent expression of AURKA (3), we tested whether differential translational efficiency of AURKA mRNA isoforms might contribute to this regulation. To avoid perturbation of translation provoked by classical cell synchronization methods (61), we used a live-cell fluorescence-based translation rate measurement assay in conjunction with a CDK2 activity sensor (62) for in silico cell cycle synchronization. We developed our assay of 'Translation Rate Imaging by rate of Protein Stabilization' (TRIPS) based on a previously introduced reporter system (63) (64).…”

Regulating the regulator: a survey of mechanisms from transcription to translation controlling expression of mammalian cell cycle kinase Aurora A

“…The number of cell cycle regulators reported to be abnormally upregulated at the translational level in disease also includes AURKA, as we will argue below. Most of our knowledge on the topic derives from studies that make use of various genome-wide methods, which in recent years have generally shed light on translational control during the cell cycle [136][137][138]. On the other hand, only few are the studies conducting gene-specific investigations on AURKA translational regulation.…”