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.

PLK1 promotes the mitotic surveillance pathway by controlling cytosolic 53BP1 availability / Burigotto, Matteo; Vigorito, Vincenza; Gliech, Colin; Mattivi, Alessia; Ghetti, Sabrina; Bisio, Alessandra; Lolli, Graziano; Holland, Andrew J; Fava, Luca. - In: EMBO REPORTS. - ISSN 1469-3178. - 24:12(2023), pp. e5723401-e5723415. [10.15252/embr.202357234]

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

Burigotto, Matteo
;
Vigorito, Vincenza;Mattivi, Alessia;Bisio, Alessandra;Lolli, Graziano;Fava, Luca
Ultimo
2023-01-01

Abstract

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
12
Burigotto, Matteo; Vigorito, Vincenza; Gliech, Colin; Mattivi, Alessia; Ghetti, Sabrina; Bisio, Alessandra; Lolli, Graziano; Holland, Andrew J; Fava, ...espandi
PLK1 promotes the mitotic surveillance pathway by controlling cytosolic 53BP1 availability / Burigotto, Matteo; Vigorito, Vincenza; Gliech, Colin; Mattivi, Alessia; Ghetti, Sabrina; Bisio, Alessandra; Lolli, Graziano; Holland, Andrew J; Fava, Luca. - In: EMBO REPORTS. - ISSN 1469-3178. - 24:12(2023), pp. e5723401-e5723415. [10.15252/embr.202357234]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11572/402195
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