| First Author | Ahmed AA | Year | 2018 |
| Journal | Environ Mol Mutagen | Volume | 59 |
| Issue | 7 | Pages | 603-612 |
| PubMed ID | 29968395 | Mgi Jnum | J:309951 |
| Mgi Id | MGI:6760511 | Doi | 10.1002/em.22206 |
| Citation | Ahmed AA, et al. (2018) Loss of DNA polymerase beta induces cellular senescence. Environ Mol Mutagen 59(7):603-612 |
| abstractText | We aim to establish that accelerated aging and premature cellular senescence seen in individuals with Down syndrome is related to reduced DNA polymerasebeta. We report here that primary fibroblasts from Down syndrome individuals exhibit greater SA-beta-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 beta expression is significantly reduced in Down syndrome primary fibroblasts (53% decline, P < 0.01). To evaluate whether DNA polymerase beta might be causative in senescence induction, we evaluated the impact of murine DNA polymerase beta nullizygosity on senescence. We find that unexposed DNA polymerase beta -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 beta 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 beta is sufficient to induce senescence. Additionally, we report a significant induction in spontaneous DNA double strand breaks in DNA polymerase beta null MEFs (fivefold increase from wild-type, P < 0.0001). Our findings strongly suggest that DNA polymerase beta is causative in senescence induction, reasonably pointing to DNA polymerase beta as a likely factor driving the premature senescence in Down syndrome. Environ. Mol. Mutagen. 59:603-612, 2018. (c) 2018 Wiley Periodicals, Inc. |
