MDC1 interacts with TOPBP1 to maintain chromosomal stability during mitosis

In mitosis, cells inactivate DNA double-strand break (DSB) repair at the chromatin level. However, some early signalling events still occur, such as recruitment of the scaffold protein MDC1 to phosphorylated histone H2AX at DSBs. Yet it remains unclear whether these events are important for maintaining genome stability during mitosis. Here, we identify a highly conserved protein interaction surface in MDC1 that is phosphorylated by CK2 and recognized by the DNA damage response mediator protein TOPBP1. Disruption of MDC1-TOPBP1 binding causes a specific loss of TOPBP1 recruitment to DSBs in mitotic but not interphase cells, accompanied by mitotic radiosensitivity, increased micronuclei and chromosomal instability. Mechanistically, we find that TOPBP1 forms filaments capable of bridging MDC1 foci in mitosis, indicating that MDC1-TOPBP1 complexes stabilize DSBs until repair is reactivated in the following G1 phase. Thus, we reveal an important, hitherto-unnoticed cooperation between MDC1 and TOPBP1 in maintaining genome stability during cell division.