Mutation in DNA Polymerase Beta Causes Spontaneous Chromosomal Instability and Inflammation-Associated Carcinogenesis in Mice

DNA polymerase beta (Pol beta) is a key enzyme in the base excision repair (BER) pathway. Pol beta is mutated in approximately 40% of human tumors in small-scale studies. The 5'-deoxyribose-5-phosphate (dRP) lyase domain of Pol beta is responsible for DNA end tailoring to remove the 5' phosphate group. We previously reported that the dRP lyase activity of Pol beta is critical to maintain DNA replication fork stability and prevent cellular transformation. In this study, we tested the hypothesis that the human gastric cancer associated variant of Pol beta (L22P) has the ability to promote spontaneous chromosomal instability and carcinogenesis in mice. We constructed a Pol beta L22P conditional knock-in mouse model and found that L22P enhances hyperproliferation and DNA double strand breaks (DSBs) in stomach cells. Moreover, mouse embryonic fibroblasts (MEFs) derived from L22P mice frequently induce abnormal numbers of chromosomes and centrosome amplification, leading to chromosome segregation errors. Importantly, L22P mice exhibit chronic inflammation accompanied by stomach tumors. These data demonstrate that the human cancer-associated variant of Pol beta can contribute to chromosomal instability and cancer development.