Control of cell proliferation by memories of mitosis

Area of Science:

• Cell Biology
• Molecular Biology
• Genetics

Background:

• Mitotic duration is critical for cellular health; extended mitosis correlates with chromosome missegregation and genomic instability.
• Problematic cells with extended mitosis pose risks to genomic integrity.

Purpose of the Study:

• To investigate the molecular mechanisms linking extended mitosis to cellular outcomes.
• To determine the role of p53-binding protein 1 (53BP1) and ubiquitin-specific protease 28 (USP28) in monitoring mitotic extension.

Main Methods:

• Analysis of protein complex formation during extended mitosis.
• Investigation of Polo-like kinase 1 (PLK1) involvement in complex assembly.
• Assessment of p53 response in G1 phase post-mitosis.
• Evaluation of cell proliferation in progeny of cells with extended mitosis.
• Correlation of mitotic monitoring ability with cancer mutations and antimitotic drug sensitivity.

Main Results:

• Extended mitosis triggers the formation of 53BP1-USP28-p53 protein complexes.
• These complexes are transmitted to daughter cells, inducing a p53-dependent G1 arrest.
• Cells experiencing threefold extended mitosis or successive shorter extensions showed proliferation arrest.
• Loss of mitotic extension monitoring was observed in p53-mutant and some p53-wild-type cancers.
• Cancers retaining mitotic monitoring were sensitive to antimitotic agents.

Conclusions:

• Mitotic extension activates a surveillance mechanism involving 53BP1, USP28, and p53 that prevents proliferation of aberrant cells.
• TP53BP1 and USP28 function as tumor suppressors by enabling mitotic monitoring.
• The ability to monitor mitotic extension is a predictive biomarker for antimitotic therapy response in cancer.