DNA double-strand breaks (DSBs) are posing serious threats to genome stability. During mitosis, cells mainly rely on polymerase theta (Polθ)-mediated repair to fix these breaks. However, how the CIP2A-TOPBP1 complex regulates this process remains unclear.

In a study published in PNAS, a team led by Prof. ZHAO Guoping from the Hefei Institutes of Physical Science of the Chinese Academy of Sciences, along with Prof. WU Lijun from Anhui University, uncovered how the protein CIP2A controls DNA repair during cell division, and influences tumor response to radiotherapy.

Researchers found that CIP2A played an essential role in mitotic DNA repair. The loss of the protein reduced DSB repair efficiency and weakened microhomology-mediated end joining. DNA damage also enhanced its interaction with Polθ, promoting the recruitment of Polθ to damaged sites.

Besides, researchers showed that CIP2A and PP2A worked together to regulate Polθ activity during repair. At the early stage, the protein maintained Polθ phosphorylation and supported its recruitment to DNA damage sites. Later, PP2A promoted Polθ dephosphorylation, allowing Polθ to be released after repair was completed.

Moreover, researchers revealed that disrupting the CIP2A-Polθ interaction increased tumor cell sensitivity to radiotherapy, especially in BRCA1/2-deficient cells.

These findings of this study reveal a new role of CIP2A in DNA repair, and suggest that targeting the CIP2A-Polθ pathway provides a new strategy for improving cancer treatment.