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 _κ ) by stabilizing its 3’UTR. 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, γH2AX foci, however overexpression of Pol _κ 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 _κ 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.