DNA polymerase kappa stabilized by Ptbp2 interacts with MRE11 and promotes genomic instability in leukemia

Polypyrimidine Tract Binding Protein 2 (Ptbp2) binds to polypyrimidine clusters in pre-mRNA molecules and plays a vital role in alternative splicing, especially during neuronal development and maturation. Our study shows that Ptbp2 binds to the 3' UTR of DNA polymerase kappa (Polk), leading to its stabilization and increased expression. While Polk's role in DNA repair is known, its post-transcriptional regulation remains largely unclear. We observed a correlation between increased Ptbp2 levels and higher Polk expression in clinical samples of Chronic Myeloid Leukemia (CML). Knocking out Ptbp2 in CML cell lines and patient samples decreased Polk levels; when treated with hydroxyurea, these samples exhibited increased DNA damage, evidenced by long comet tails and elevated γH2AX foci, a DNA damage marker; however, re-expressing Polk in Ptbp2-KO cells restored the phenotype. Disruption of the DNA repair pathway is a hallmark of cancer and is closely linked to genomic instability. Polk was found to interact with MRE11 of the MRN complex, regulating the activation of the ATM-CHK2 signaling pathway. Cells with high levels of Ptbp2 and Polk showed increased sister chromatid exchanges and BrdU incorporation in ex vivo tests, while multinucleated cells with multipolar spindles appeared in in vivo tests. Our results confirm the key role of the Ptbp2-Polk-MRE11 axis in promoting genomic instability and supporting the survival of cells with higher malignancy.