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

Xipeng Zhao1,2,3, Bin Chen4,5, Feng Xu1,3

  • 1High Magnetic Field Laboratory, Key Laboratory of High Magnetic Field and Ion Beam Physical Biology, Chinese Academy of Sciences, Hefei, Anhui 230031, China.

Proceedings of the National Academy of Sciences of the United States of America
|August 3, 2026
PubMed

Insights

The CIP2A-TOPBP1 complex collaborates with Polθ to efficiently repair DNA double-strand breaks during mitosis. This interaction is crucial for cancer treatment strategies, particularly in BRCA1/2-deficient cells undergoing radiotherapy.

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Genetics

Background:

  • DNA double-strand breaks (DSBs) are critical DNA lesions.
  • Mitotic DSB repair primarily involves Polθ-mediated microhomology-mediated end joining (MMEJ).
  • The role of the CIP2A-TOPBP1 complex in DSB repair coordination with Polθ was previously unclear.

Purpose of the Study:

  • To investigate the functional relationship between the CIP2A-TOPBP1 complex and Polθ in mitotic DSB repair.
  • To elucidate the mechanism by which CIP2A-TOPBP1 regulates Polθ activity and localization.
  • To explore the therapeutic implications of the CIP2A-Polθ interaction in cancer.

Main Methods:

  • Immunofluorescence and co-immunoprecipitation assays to study protein interactions and localization.
  • Cellular assays to assess DNA repair efficiency, phosphorylation status, and cell viability.
  • Analysis of tumor growth and synthetic lethality in cancer models.

Main Results:

  • CIP2A-TOPBP1 complex is recruited to mitotic DSB sites and directly interacts with Polθ.
  • CIP2A inhibits PP2A phosphatase, sustaining Polθ phosphorylation and prolonging its chromatin retention for efficient repair.
  • Loss of CIP2A impairs tumor growth; disruption of CIP2A-Polθ binding causes persistent DNA damage and synthetic lethality in BRCA1/2-deficient cells.

Conclusions:

  • CIP2A-TOPBP1 dynamically regulates Polθ function in mitotic DSB repair through a cooperative mechanism.
  • This pathway offers potential synthetic lethal strategies for cancer therapy, especially in combination with radiotherapy for BRCA1/2-deficient cancers.
Keywords:
CIP2A–TOPBP1 complexDNA polymerase theta (Polθ)PP2A-mediated dephosphorylationgenome stabilitymitotic DNA double-strand break repair

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