TopBP1 coordinates MiDAS via phosphorylation- and SUMOylation-dependent recruitment of SLX4

Kamilla Vandsø Petersen, Postdoc, Department of Biology, University of Copenhagen

The majority of cancer cells experience replication stress, which ultimately causes them to enter mitosis with underreplicated DNA. To counteract this, cells use a mechanism known as mitotic DNA synthesis (MiDAS), which completes replication of underreplicated DNA in early mitosis. MiDAS is considered an Achilles heel of highly replicative cancers because these cells rely on it for survival. We show that human TopBP1 localizes to sites of underreplicated DNA marked by FANCD2 and promotes MiDAS by recruiting the nuclease scaffold protein SLX4. Recruitment of SLX4 to TopBP1 foci in mitosis requires TopBP1-K704, SLX4-T1260, and several SUMO-interaction motifs in SLX4. It may also be facilitated by the phase separation properties of both TopBP1 and SLX4. Finally, we show that recruitment of SLX4 to TopBP1 foci in mitosis is important to prevent DNA damage from being transmitted to daughter cells. Based on these findings, we propose that disrupting the TopBP1–SLX4 interaction during mitosis could be a potential strategy for anti-cancer therapy.