DNA polymerase β (Pol β) is a key enzyme in DNA base excision repair (BER)， a pathway that maintains genome integrity and stability. Pol β mutations have been detected in various types of cancers， suggesting a possible linkage between Pol β mutations and cancer. However， it is not clear whether and how Pol β mutations cause cancer onset and progression. In the current work， we show that a substitution mutation， R152C， impairs Pol β polymerase activity and BER efficiency. Cells harboring Pol β 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 β R152C can drive cellular transformation.