PLK1 promotes the mitotic surveillance pathway by controlling cytosolic 53BP1 availability.

Autor: Burigotto M; Armenise-Harvard Laboratory of Cell Division, Department of Cellular, Computational and Integrative Biology - CIBIO, University of Trento, Trento, Italy., Vigorito V; Armenise-Harvard Laboratory of Cell Division, Department of Cellular, Computational and Integrative Biology - CIBIO, University of Trento, Trento, Italy., Gliech C; Department of Molecular Biology and Genetics, Johns Hopkins University School of Medicine, Baltimore, MD, USA., Mattivi A; Armenise-Harvard Laboratory of Cell Division, Department of Cellular, Computational and Integrative Biology - CIBIO, University of Trento, Trento, Italy., Ghetti S; Armenise-Harvard Laboratory of Cell Division, Department of Cellular, Computational and Integrative Biology - CIBIO, University of Trento, Trento, Italy., Bisio A; Laboratory of Radiobiology, Department of Cellular, Computational and Integrative Biology - CIBIO, University of Trento, Trento, Italy., Lolli G; Laboratory of Protein Crystallography and Structure-Based Drug Design, Department of Cellular, Computational and Integrative Biology - CIBIO, University of Trento, Trento, Italy., Holland AJ; Oncology Research, Amgen Research, Thousand Oaks, CA, USA., Fava LL; Armenise-Harvard Laboratory of Cell Division, Department of Cellular, Computational and Integrative Biology - CIBIO, University of Trento, Trento, Italy.
Jazyk: angličtina
Zdroj: EMBO reports [EMBO Rep] 2023 Dec 06; Vol. 24 (12), pp. e57234. Date of Electronic Publication: 2023 Oct 27.
DOI: 10.15252/embr.202357234
Abstrakt: 53BP1 acts at the crossroads between DNA repair and p53-mediated stress response. With its interactors p53 and USP28, it is part of the mitotic surveillance (or mitotic stopwatch) pathway (MSP), a sensor that monitors the duration of cell division, promoting p53-dependent cell cycle arrest when a critical time threshold is surpassed. Here, we show that Polo-like kinase 1 (PLK1) activity is essential for the time-dependent release of 53BP1 from kinetochores. PLK1 inhibition, which leads to 53BP1 persistence at kinetochores, prevents cytosolic 53BP1 association with p53 and results in a blunted MSP. Strikingly, the identification of CENP-F as the kinetochore docking partner of 53BP1 enabled us to show that measurement of mitotic timing by the MSP does not take place at kinetochores, as perturbing CENP-F-53BP1 binding had no measurable impact on the MSP. Taken together, we propose that PLK1 supports the MSP by generating a cytosolic pool of 53BP1 and that an unknown cytosolic mechanism enables the measurement of mitotic duration.
(© 2023 The Authors. Published under the terms of the CC BY 4.0 license.)
Databáze: MEDLINE
Externí odkaz: