The mitotic surveillance pathway requires PLK1-dependent 53BP1 displacement from kinetochores

Burigotto, M.; Vigorito, V.; Mattivi, A.; Gliech, C.; Ghetti, S.; Bisio, A.; Lolli, G.; Holland, A. J.; Fava, L. L.

doi:10.1101/2023.03.27.534346

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bioRxiv · 10.1101/2023.03.27.534346

The mitotic surveillance pathway requires PLK1-dependent 53BP1 displacement from kinetochores

Burigotto, M.·Vigorito, V.·Mattivi, A.·Gliech, C.·Ghetti, S.·Bisio, A.·Lolli, G.·Holland, A. J.·Fava, L. L.

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Abstract

53BP1 acts at the crossroads between DNA repair and p53-mediated stress response. With its interactor USP28, it is part of the mitotic surveillance pathway (MSP), a sensor that monitors the duration of cell division, promoting p53-dependent cell cycle arrest when a critical time threshold is surpassed. 53BP1 dynamically associates with kinetochores, being recruited during prophase, and then undergoing a time-dependent loss of affinity. However, the relevance of this behaviour remains unclear. Here, we identify CENP-F as an interaction partner and kinetochore receptor for 53BP1. By engineering human cells with a CENP-F point mutation, we demonstrate that preventing 53BP1 kinetochore localization does not reduce MSP proficiency. Strikingly, however, preventing the loss of 53BP1 from the kinetochore by inhibiting Polo-like kinase 1 (PLK1) restrains MSP activity, a phenomenon that is abrogated in the CENP-F mutant condition. Taken together, we demonstrate that kinetochore-loaded 53BP1 represents an MSP functionally inhibited state and that PLK1-dependent re-localization of 53BP1 represents an important layer of MSP regulation.

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Burigotto, M., Vigorito, V., Mattivi, A., Gliech, C., Ghetti, S., Bisio, A., Lolli, G., Holland, A. J., Fava, L. L.. 2023-03-27. The mitotic surveillance pathway requires PLK1-dependent 53BP1 displacement from kinetochores. https://doi.org/10.1101/2023.03.27.534346

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