title: Reciprocal Regulation between 53BP1 and the Anaphase-Promoting Complex/Cyclosome Is Required for Genomic Stability during Mitotic Stress.
abstract: The anaphase-promoting complex/cyclosome (APC/C) is an E3 ubiquitin ligase that targets substrates for degradation to promote mitotic progression. Here, we show that the DNA damage response protein 53BP1 contains conserved KEN boxes that are required for APC/C-dependent degradation in early mitosis. Mutation of the 53BP1 KEN boxes stabilized the protein and extended mitotic duration, whereas 53BP1 knockdown resulted in a shorter and delayed mitosis. Loss of 53BP1 increased APC/C activity, and we show that 53BP1 is a direct APC/C inhibitor. Although 53BP1 function is not absolutely required for normal cell cycle progression, knockdown was highly toxic in combination with mitotic spindle poisons. Moreover, chemical inhibition of the APC/C was able to rescue the lethality of 53BP1 loss. Our findings reveal a reciprocal regulation between 53BP1 and APC/C that is required for response to mitotic stress and may contribute to the tumor-suppressor functions of 53BP1.
authors.affiliation: Goodman Cancer Research Centre, McGill University, Montreal, QC H3A 1A3, Canada; Department of Biochemistry, McGill University, Montreal, QC H3G 1Y6, Canada.
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Kucharski
authors.affiliation: School of Cancer and Genomic Sciences, College of Medical and Dental Sciences, The University of Birmingham, Edgbaston, Birmingham B15 2TT, UK.
authors.forename: Paul E
authors.initials: PE
authors.lastname: Minshall
authors.affiliation: Goodman Cancer Research Centre, McGill University, Montreal, QC H3A 1A3, Canada; Department of Biochemistry, McGill University, Montreal, QC H3G 1Y6, Canada.
authors.forename: Mohamed
authors.initials: M
authors.lastname: Moustafa-Kamal
authors.affiliation: School of Cancer and Genomic Sciences, College of Medical and Dental Sciences, The University of Birmingham, Edgbaston, Birmingham B15 2TT, UK.
authors.forename: Andrew S
authors.initials: AS
authors.lastname: Turnell
authors.affiliation: Goodman Cancer Research Centre, McGill University, Montreal, QC H3A 1A3, Canada; Department of Biochemistry, McGill University, Montreal, QC H3G 1Y6, Canada; Department of Microbiology and Immunology, Montreal, QC H3A 2B4, Canada. Electronic address: jose.teodoro@mcgill.ca.
authors.forename: Jose G
authors.initials: JG
authors.lastname: Teodoro
mesh_terms: D064173:Anaphase-Promoting Complex-Cyclosome / Q000378:metabolism*; D018797:Cell Cycle Proteins / Q000378:metabolism; D002460:Cell Line; D045744:Cell Line, Tumor; D042822:Genomic Instability / Q000235:genetics*; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D008938:Mitosis / Q000235:genetics*; D008941:Spindle Apparatus / Q000378:metabolism; D000071857:Tumor Suppressor p53-Binding Protein 1 / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism
chemical_list: D018797:Cell Cycle Proteins; C498301:TP53BP1 protein, human; D000071857:Tumor Suppressor p53-Binding Protein 1; D064173:Anaphase-Promoting Complex-Cyclosome; D044767:Ubiquitin-Protein Ligases
keywords: 53BP1; anaphase-promoting complex/cyclosome; mitosis; spindle poison; ubiquitin