Abstract 3590: A Neil1 DNA glycosylase germline variant induces genomic instability and cellular transformation

Abstract

Abstract NEIL1 DNA glycosylase is a bifunctional enzyme that recognizes oxidized pyrimidines and formamidopyrimidines, and appears to remove damage in advance of the replication fork. The rs5745906 SNP of the NEIL1 gene has a minor allele frequency of 1% and is a G to A base substitution that encodes the G83D NEIL1 protein. Interestingly, this mutation is also present in cholangiocarcinomas. Unlike WT NEIL1, the G83D variant is not able to recognize oxidized bases efficiently due to a shift in the void filling residues that stabilize the DNA duplex once a damaged base has been extruded into the glycosylase substrate binding pocket. The goal of our study was to determine if the G83D NEIL1 variant exhibits a cancer-related phenotype in cells. We found that unlike wild-type (WT) NEIL1, expression of G83D in MCF10A immortal human breast epithelial cells induces genomic instability and cellular transformation. Expression of G83D but not WT NEIL1, in MCF10A cells leads to replication fork stalling and slow replication fork velocity. Our results suggest that G83D is unable to remove oxidative DNA damage at the replication fork, resulting in genomic instability and cellular transformation. Our results are consistent with the idea that individuals who harbor the G83D NEIL1 variant are at increased risk for cancer. Citation Format: Joann B. Sweasy, Heather Galick, Scott Kathe, Susan Wallace. A Neil1 DNA glycosylase germline variant induces genomic instability and cellular transformation. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3590.