The accurate repair of DNA double-strand breaks (DSBs), highly toxic DNA lesions, is crucial for genome integrity and is tightly regulated during the cell cycle. In mitosis, cells inactivate DSB repair in favor of a tethering mechanism that stabilizes broken chromosomes until they are repaired in the subsequent cell cycle phases. How this is achieved mechanistically is not yet understood, but the adaptor protein TOPBP1 is critically implicated in this process. Here, we identify CIP2A as a TOPBP1-interacting protein that regulates TOPBP1 localization specifically in mitosis. Cells lacking CIP2A display increased radio-sensitivity, micronuclei formation and chromosomal instability. CIP2A is actively exported from the cell nucleus in interphase but, upon nuclear envelope breakdown at the onset of mitosis, gains access to chromatin where it forms a complex with MDC1 and TOPBP1 to promote TOPBP1 recruitment to sites of mitotic DSBs. Collectively, our data uncover CIP2A-TOPBP1 as a mitosis-specific genome maintenance complex.

DNA 双链断裂 (DSB) 和高毒性 DNA 损伤的准确修复对于基因组完整性至关重要，并且在细胞周期中受到严格调控。在有丝分裂中，细胞使 DSB 修复失活，转而采用一种束缚机制来稳定断裂的染色体，直到它们在随后的细胞周期阶段得到修复。这一过程是如何实现的尚不清楚，但衔接蛋白 TOPBP1 在这一过程中起着至关重要的作用。在这里，我们将 CIP2A 确定为 TOPBP1 相互作用蛋白，可特异性调节有丝分裂中的 TOPBP1 定位。缺乏 CIP2A 的细胞表现出放射敏感性、微核形成和染色体不稳定性增加。 CIP2A 在间期从细胞核中主动输出，但在有丝分裂开始时核膜破裂时，可以进入染色质，与 MDC1 和 TOPBP1 形成复合物，以促进 TOPBP1 募集到有丝分裂 DSB 位点。总的来说，我们的数据揭示了 CIP2A-TOPBP1 作为有丝分裂特异性基因组维持复合体。