TOPBP1-PLK1 interaction preserves genome integrity during mitosis

TOPBP1 is a scaffold protein with multiple functions in genome integrity. During mitosis, TOPBP1 is coordinating DNA repair and genome maintenance, thereby reducing 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 remain unclear. Mitotic kinases are involved in regulating genome maintenance pathways during mitosis. Indeed, TOPBP1 binds the mitotic kinase PLK1, but the molecular aspects as well as the functional significance of this is unclear. To address this, we here identify and characterize a conserved CDK1-primed binding site for PLK1 in TOPBP1. We show that mutation of this results in increased transmission of DNA damage to G1 daughter cells, deficient mitotic DNA repair synthesis, mislocalization of DNA polymerase θ, and increased frequency of anaphase bridges and micronucleation. Consistent with this, BRCA2 depleted cells are highly dependent on TOPBP1-PLK1 complex formation. Altogether, we reveal the molecular details of TOPBP1-PLK1 complex formation and address its role in genome maintenance during mitosis.