CIP2A tetramerization is required for mitotic DNA repair

DNA damage that accumulates during cell division can compromise the integrity of an organism's genetic material. To combat this, a protein complex known as TOPBP1-CIP2A is recruited to damaged regions on chromosomes within dividing cells. This complex, composed of the proteins TOPBP1 and CIP2A, plays a crucial role in repairing these lesions and preventing the formation of abnormal structures called micronuclei.

While the importance of CIP2A in this process has been recognized, its precise function has remained unclear. Recent research has shed light on CIP2A's role, revealing how its molecular structure enables it to function effectively in the cell. Researchers have determined that CIP2A exists as tetramers, or groups of four molecules, which assemble through specific interactions at the protein's C-terminal region.

The formation of these tetramers is essential for the correct positioning and activation of a DNA repair enzyme called polymerase theta (POLQ) at sites of DNA damage during mitosis. Without proper tetramerization, POLQ cannot be effectively recruited to the damaged DNA, leading to increased risk of genomic instability and cell death, particularly in cancer cells that are already prone to DNA replication errors due to defects in genes like BRCA1/2.

The study's findings emphasize that CIP2A tetramers serve as a critical scaffold for the assembly of the mitotic DNA repair machinery, ensuring that replication-born DNA lesions are accurately repaired and preventing the formation of harmful micronuclei.