Ribosomal Stress Induces Cell Cycle Arrest After Prolonged Mitosis

Mitosis is a highly regulated process aimed to separate duplicated chromosomes equally into two daughter cells.Perturbation of mitosis leads to cell cycle arrest mostly because mis-segregation of chromosomes and DNA damage induced during mitosis or cytokinesis.Interestingly,after a short prolongation of prometaphase or metaphase, where there is no DNA damage or mis-segragation of chromosomes in daughter cells and the mitosis completion is normal,cells that spent more than 1.5hrs arrest in G1 phase with evident p53 activation.Here,we report that ribosomal stress pathway is responsible for the stabilization of tumor suppressor p53 after prolonged mitosis. First,we find that cells spend more than 1.5hrs show strong activation of p53 and p38 compared with those spend less time.Since p38 MAPK can phosphorylate p53 directly,we next test the possibility of stabilization of p53 is mediated by activated p38 and the results show that p53 is stabilized in a p38 independent way. Then we focused on the activation of p53 pathway.The p53 tumor suppressor is activated under various cellular stress especially when genome integrity is impaired,which is not the case in our experiment.Another major cause of p53 activation is ribosomal stress.When ribosome biogenesis is impaired,ribosome sub-units translocate from nucleolus to nucleoplasma and interact with MDM2,the p53 specific E3 ubiquitin ligase, thus causes p53 stabilization.During mitosis,nucleolus is disassembled and rRNA transcription is inhibited.whether prolonged inhibition of ribosome biogenesis during mitosis causes p53 stabilization is unknown.After knocking down ribosome sub-unit Rp111,we found that p53 stabilization is inhibited.In conclusion,our findings suggest that perturbation of mitosis induces ribosomal stress leading to p53 stabilization and the upstream signal needs further investigation.