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bioRxiv · 10.1101/2022.03.30.486397

A conserved PLK1 docking site in TopBP1 maintains genome integrity during mitosis

Li, J.·Bagge, J. V.·Lisby, M.·Nilsson, J.·Oestergaard, V. H.
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Abstract

TopBP1 is a large scaffold protein with multiple functions in genome integrity. We previously identified a novel role for TopBP1 during M phase by showing that TopBP1 reduces carry-over of DNA damage to daughter cells. This function emerges as a critical backup pathway in BRCA deficient cells, yet many aspects of TopBP1 regulation during mitosis are unclear. The mitotic kinase PLK1 has been reported to interact with TopBP1 but the functional relevance of this is unclear. Here, we identify and characterize a conserved PLK1 docking site in TopBP1. Endogenous deletion of the PLK1 docking site in TopBP1 results in increased number of mitotic TopBP1 foci, increased DNA damage in daughter cells, deficient mitotic DNA repair synthesis and increased frequency of binucleation. At the same time, cell cycle distribution and ATR activation are normal in cells with the PLK1 docking site deletion in TopBP1. Interestingly, mutation of this site in TopBP1 renders cells sensitive to PARP inhibitors but not to camptothecin hinting to different cellular effects of the two chemotherapeutics. Altogether, our data indicate that the PLK1-TopBP1 interaction is critical for the mitotic function of TopBP1.

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Li, J., Bagge, J. V., Lisby, M., Nilsson, J., Oestergaard, V. H.. 2022-03-30. A conserved PLK1 docking site in TopBP1 maintains genome integrity during mitosis. https://doi.org/10.1101/2022.03.30.486397

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