R152C DNA Pol β mutation impairs base excision repair and induces cellular transformation.

DNA polymerase beta (Pol beta) is a key enzyme in DNA base excision repair (BER), a pathway that maintains genome integrity and stability. Pol beta mutations have been detected in various types of cancers, suggesting a possible linkage between Pol beta mutations and cancer. However, it is not clear whether and how Pol beta mutations cause cancer onset and progression. In the current work, we show that a substitution mutation, R152C, impairs Pol beta polymerase activity and BER efficiency. Cells harboring Pol beta R152C are sensitive to the DNA damaging agents methyl methanesulfonate (MMS) and H2O2. Moreover, the mutant cells display a high frequency of chromatid breakages and aneuploidy and also form foci. Taken together, our data indicate that Pol beta R152C can drive cellular transformation.