TopBP1 coordinates DNA repair synthesis in mitosis via recruitment of the nuclease scaffold SLX4

Authors:

Jonas Bagge, Kamilla Vandsø Petersen, Sinem N. Karakus, Thorbjørn M. Nielsen, Johanne Rask, Christian R. Brøgger, Jonas Jensen, Meliti Skouteri, Antony M. Carr, Ivo A. Hendriks, Vibe H. Oestergaard, Michael Lisby

Keywords:

DNA damage; DNA repair; Mitosis; Cancer; replication stress; MiDAS;

Abstract:

The majority of cancer cells experience replication stress, which ultimately causes them to enter mitosis with underreplicated DNA. To alleviate the consequences of replication stress, cells utilize a mechanism known as MiDAS that functions to complete synthesis of underreplicated DNA in early mitosis. This process is considered an Achilles heel for highly replicative cancers. In this study, we show that human TopBP1 localizes to sites of underreplicated DNA marked by FANCD2 and promotes MiDAS through recruitment of the nuclease scaffold protein SLX4. Additionally, we demonstrate that the recruitment of SLX4 to TopBP1 foci in mitosis depends on TopBP1-K704, SLX4-T1260, and several SUMO-interaction motifs in SLX4. Lastly, we show that the recruitment of SLX4 to TopBP1 foci in mitosis is important to prevent transmission of DNA damage to daughter cells. Based on this, we hypothesize that targeting the TopBP1-SLX4 interaction in mitosis may be a potential strategy for anti-cancer therapy.

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