RRC ID 39660
Author Meitinger F, Anzola JV, Kaulich M, Richardson A, Stender JD, Benner C, Glass CK, Dowdy SF, Desai A, Shiau AK, Oegema K.
Title 53BP1 and USP28 mediate p53 activation and G1 arrest after centrosome loss or extended mitotic duration.
Journal J Cell Biol
Abstract In normal human cells, centrosome loss induced by centrinone-a specific centrosome duplication inhibitor-leads to irreversible, p53-dependent G1 arrest by an unknown mechanism. A genome-wide CRISPR/Cas9 screen for centrinone resistance identified genes encoding the p53-binding protein 53BP1, the deubiquitinase USP28, and the ubiquitin ligase TRIM37. Deletion of TP53BP1, USP28, or TRIM37 prevented p53 elevation in response to centrosome loss but did not affect cytokinesis failure-induced arrest or p53 elevation after doxorubicin-induced DNA damage. Deletion of TP53BP1 and USP28, but not TRIM37, prevented growth arrest in response to prolonged mitotic duration. TRIM37 knockout cells formed ectopic centrosomal-component foci that suppressed mitotic defects associated with centrosome loss. TP53BP1 and USP28 knockouts exhibited compromised proliferation after centrosome removal, suggesting that centrosome-independent proliferation is not conferred solely by the inability to sense centrosome loss. Thus, analysis of centrinone resistance identified a 53BP1-USP28 module as critical for communicating mitotic challenges to the p53 circuit and TRIM37 as an enforcer of the singularity of centrosome assembly.
Volume 214(2)
Pages 155-66
Published 2016-7-18
DOI 10.1083/jcb.201604081
PII jcb.201604081
PMID 27432897
PMC PMC4949453
MeSH Biomarkers / metabolism CRISPR-Cas Systems / genetics Cell Line Cell Proliferation / drug effects Centrosome / drug effects Centrosome / metabolism* G1 Phase Cell Cycle Checkpoints* / drug effects Gene Deletion Gene Knockout Techniques Genetic Testing Humans Mitosis* / drug effects Mutation / genetics Nuclear Proteins / metabolism Pyrimidines / pharmacology Sulfones / pharmacology Tripartite Motif Proteins Tumor Suppressor Protein p53 / metabolism* Tumor Suppressor p53-Binding Protein 1 / metabolism* Ubiquitin Thiolesterase / metabolism* Ubiquitin-Protein Ligases
IF 8.811
Times Cited 70
DNA material pCAG-HIVgp (RDB04394) pCMV-VSV-G-RSV-Rev (RDB04393).