DNA polymerase beta (Pol β) is a key enzyme for the protection of oxidative DNA lesions via its role in base excision repair (BER). Approximately 1/3 of tumors studied to date express Pol β variant proteins, and several tumors overexpress Pol β. Pol β possesses DNA polymerase and dRP lyase activities, both of which are known to be important for efficient BER. The dRP lyase activity resides within the 8kDa amino terminal domain of pol β, is responsible for removal of the 5′ phosphate group and the polymerase domain at subsequent steps fills the gaps. Previously, we demonstrated that gastric cancer-associated variant of pol β (Leu22Pro (L22P)) lacks dRP lyase function in-vitro. Here, we have employed DNA fiber labeling to quantify, for the first time, the extent to which the normal function of dRP lyase of DNA polymerase beta is critical to maintain global replication fork rates in normal gastric epithelial cells. We report that replication fork rates in L22P expressing cells are on average half of those observed with wild-type cells. In addition, we show that L22P variant promotes replication dependent double strand breaks that may likely responsible for chromosomal aberrations. These data may implicate normal function of dRP lyase is critical to stabilize replication fork stall and prevent replication fork collapse to DNA double strand breaks.

Citation Format: Dawit Kidane, Jenna Rozacky, Joann B. Sweasy. Gastric cancer associated variant of DNA polymerase Beta (Leu22Pro) induce genomic instability and cellular transformation. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3026. doi:10.1158/1538-7445.AM2015-3026