DNA polymerase kappa stabilized by PTBP2 interacts with MRE11 and promotes genomic instability in leukemia cells

Polypyrimidine tract binding protein 2 (PTBP2) is an RNA-binding protein that controls alternative splicing in neuronal, muscle, and Sertoli cells. Our study unveils a novel role of PTBP2 in promoting the excessive production of the DNA polymerase kappa (Pol{kappa}) by stabilizing its 3UTR. We observed an association between its increased expression and the upregulation of PTBP2 in clinical samples of Chronic Myeloid Leukemia (CML). Ptbp2 knock-out CML cell lines and patient samples treated with hydroxyurea presented with increased DNA damage, as evidenced by long comet tails and higher levels of the DNA damage marker, {gamma}H2AX foci, however overexpression of Pol{kappa} in the Ptbp2-KO cells restored normal phenotype. The deregulation of the DNA repair pathway is a defining feature of malignancies and is closely associated with genomic instability. POLK was found to interact with MRE11 of the MRN complex, thereby governing the activation of ATM-CHK2. Cells with elevated levels of Ptbp2 and Pol{kappa} demonstrated increased sister chromatid exchange and BrdU incorporation in ex-vivo assays, while multinucleated cells with multipolar spindles were observed in in-vivo assays. Our findings confirm the critical role of the PTBP2-POLK axis in driving genomic instability and bolstering the viability of cells with increased malignancy.