CIP2A-TOPBP1 complex and PP2A dynamically regulate Polθ recruitment and phosphorylation at mitotic DNA double-strand breaks

• 成果类型: Article
• 署名作者: Zhao, Xipeng; Chen, Bin; Xu, Feng; Zhang, Jie; Yao, Zhicheng; Wang, Ruru; Zhou, Shenglan; Hou, Yao; Xu, Shangkun; Xu, An; Wu, Lijun; Zhao, Guoping
• 署名单位: Chinese Academy of Sciences; Hefei Institutes of Physical Science, CAS; Chinese Academy of Sciences; University of Science & Technology of China, CAS; Chinese Academy of Sciences; Hefei Institutes of Physical Science, CAS; Mayo Clinic; Anhui University; Anhui Medical University
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.2600248123
• 发表日期: 2026-08-11
• 页码: e2600248123
• 关键词: mitotic DNA double-strand break repair; CIP2A-TOPBP1 complex; DNA polymerase theta (Pol theta); PP2A-mediated dephosphorylation; genome stability; CIP2A; polymerase; repair; dephosphorylation; oncoprotein; mechanism; enables; cells

摘要

DNA double-strand breaks (DSBs) that occur during mitosis are primarily repaired by Pol theta-mediated microhomology-mediated end joining (MMEJ). The CIP2A-TOPBP1 complex has been shown to tether broken chromatin at mitotic DSBs, but whether it coordinates with or functions independently of Pol theta remains unknown. Here, we show that the CIP2A-TOPBP1 complex is recruited to mitotic DSB sites, where it directly interacts with Pol theta and corecruits Pol theta to chromatin. CIP2A sustains Pol theta phosphorylation by inhibiting PP2A, thereby prolonging Pol theta chromatin retention and enabling efficient repair. Upon repair completion, the CIP2A-TOPBP1 complex dissociates, PP2A dephosphorylates Pol theta, and Pol theta is released from chromatin. Loss of CIP2A impairs tumor growth, while disruption of CIP2A-Pol theta binding leads to persistent DNA damage, micronucleus formation, and synthetic lethality in BRCA1/2-deficient cells. These findings uncover a cooperative mechanism by which CIP2A-TOPBP1 dynamically regulates Pol theta in mitotic DSB repair and provide insights into the synthetic lethal interaction of CIP2A with BRCA1/2 under radiotherapy.