Loss of DNA polymerase induces cellular senescence

We aim to establish that accelerated aging and premature cellular senescence seen in individuals with Down syndrome is related to reduced DNA polymerase. We report here that primary fibroblasts from Down syndrome individuals exhibit greater SA--gal staining (fourfold increase, P<0.001), increased p16 transcript abundance (threefold increase, P<0.01), and reduced HMGB1 nuclear localization (1.5-fold lower, P<0.01). We also find that DNA polymerase expression is significantly reduced in Down syndrome primary fibroblasts (53% decline, P<0.01). To evaluate whether DNA polymerase might be causative in senescence induction, we evaluated the impact of murine DNA polymerase nullizygosity on senescence. We find that unexposed DNA polymerase -null primary fibroblasts exhibit a robust increase in the number of senescent cells compared to wild-type (11-fold, P<0.001), demonstrating that loss DNA polymerase is sufficient to induce senescence. We also see an additional increase in response to hydroxyurea (threefold greater than WT-HU, P<0.05). These data demonstrate that loss of DNA polymerase is sufficient to induce senescence. Additionally, we report a significant induction in spontaneous DNA double strand breaks in DNA polymerase null MEFs (fivefold increase from wild-type, P<0.0001). Our findings strongly suggest that DNA polymerase is causative in senescence induction, reasonably pointing to DNA polymerase as a likely factor driving the premature senescence in Down syndrome. Environ. Mol. Mutagen. 59:603-612, 2018. (c) 2018 Wiley Periodicals, Inc.