Department of Gynecology, University of Zurich and University Hospital Zurich, Schlieren, Switzerland.
Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON, Canada.
Nat Commun. 2022 Jul 16;13(1):4143. doi: 10.1038/s41467-022-31865-5.
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.
准确修复双链 DNA 断裂（DSBs）这种剧毒的 DNA 损伤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。在有丝分裂过程中，细胞会抑制 DSB 修复，转而采用一种连接机制，以稳定断裂的染色体，直到在下一个细胞周期阶段进行修复。然而，目前尚不清楚这一过程在机制上是如何实现的，但衔接蛋白 TOPBP1 在此过程中起着关键作用。在这里，我们鉴定出 CIP2A 是 TOPBP1 的相互作用蛋白，它可特异性调节有丝分裂过程中 TOPBP1 的定位。缺乏 CIP2A 的细胞表现出更高的放射敏感性、微核形成和染色体不稳定性。CIP2A 在细胞间期中被主动输出细胞核，但在有丝分裂开始时核膜破裂后，它能够进入染色质，在那里与 MDC1 和 TOPBP1 形成复合物，促进 TOPBP1 募集到有丝分裂 DSB 部位。总的来说，我们的数据揭示了 CIP2A-TOPBP1 是一个有丝分裂特异性的基因组维护复合物。
