Subsequent steps may follow either of two distinct BER subpathways that replace either a single nucleotide (short-patch BER) or multiple nucleotides (long-patch BER). BER is initiated by excision of damaged bases by DNA glycosylases which generate an abasic site. These data demonstrate that the human cancer-associated variant of Pol β can contribute to chromosomal instability and cancer development.īase excision repair (BER) is the predominant pathway in cells for preventing mutations associated with oxidative and alkylating DNA damage. Importantly, L22P mice exhibit chronic inflammation accompanied by stomach tumors. Moreover, mouse embryonic fibroblasts (MEFs) derived from L22P mice frequently induce abnormal numbers of chromosomes and centrosome amplification, leading to chromosome segregation errors. We constructed a Pol β L22P conditional knock-in mouse model and found that L22P enhances hyperproliferation and DNA double strand breaks (DSBs) in stomach cells. In this study, we tested the hypothesis that the human gastric cancer associated variant of Pol β (L22P) has the ability to promote spontaneous chromosomal instability and carcinogenesis in mice. We previously reported that the dRP lyase activity of Pol β is critical to maintain DNA replication fork stability and prevent cellular transformation. The 5´-deoxyribose-5-phosphate (dRP) lyase domain of Pol β is responsible for DNA end tailoring to remove the 5’ phosphate group. Pol β is mutated in approximately 40% of human tumors in small-scale studies. DNA polymerase beta (Pol β) is a key enzyme in the base excision repair (BER) pathway.

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