A research team led by Prof. ZHAO Guoping at the Hefei Institutes of Physical Science of the Chinese Academy of Sciences, in collaboration with Prof. WU Lijun at Anhui University, has uncovered how the protein CIP2A controls DNA repair during cell division and influences tumor response to radiotherapy.
The study showed that the CIP2A-TOPBP1 complex works with the phosphatase PP2A to regulate the recruitment and activity of DNA polymerase theta (Polθ) at damaged DNA sites during mitosis.
The findings were published in Proceedings of the National Academy of Sciences of the United States of America.
DNA double-strand breaks are serious threats to genome stability. During mitosis, cells mainly rely on Polθ-mediated repair to fix these breaks. However, how the CIP2A-TOPBP1 complex regulates this process has remained unclear.
The researchers found that CIP2A plays an essential role in mitotic DNA repair. 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.
Further experiments showed that CIP2A and PP2A work together to regulate Polθ activity during repair. At the early stage, the protein maintains Polθ phosphorylation and supports its recruitment to DNA damage sites. Later, PP2A promotes Polθ dephosphorylation, allowing Polθ to be released after repair is completed.
The researchers further found that disrupting the CIP2A-Polθ interaction increased tumor cell sensitivity to radiotherapy, especially in BRCA1/2-deficient cells.
These findings reveal a previously unknown role of CIP2A in DNA repair and suggest that targeting the CIP2A-Polθ pathway could provide a new strategy for improving cancer treatment.
CIP2A-mediated mitotic Microhomology-Mediated End Joining repair (Image by ZHAO Guoping)
