We generated DT40 cells in which both alleles of the SIRT6 are inactivated by gene targeting. To test the role of SIRT6 in DNA repair we tested the sensitivity of these cell lines towards DNA damaging agents. In contrast to previous reports in murine embryonic stem cells and murine embryonic fibroblasts, SIRT6-deficient DT40 cells show normal sensitivity towards hydrogen peroxide, MMS, and cisplatin treatment. Furthermore, SHM and GCV are unaffected, suggesting that SIRT6 does not play a critical role in DNA repair in this B-cell line. We determined, however, that SIRT6 is important for the control of global gene expression. Microarray studies showed and misregulation of hundreds on genes, and chromatin immunoprecipitation (ChIP) experiments link this observation to changes in histone acetylation patterns. ChIP-Sequencing are currently performed to identify the important target genes of SIRT6. These findings are consistent with a recent report of SIRT6 being important for the activation of NFkappaB target genes. Overall we expect to gain insight into the genetic pathways that are controlled by SIRT6, and how this contributes to controlling responses to stimuli (including stress) and ultimately regulating organismal lifespan.
| Yasuda, M; Wilson, D R; Fugmann, S D et al. (2011) Synthesis and characterization of SIRT6 protein coated magnetic beads: identification of a novel inhibitor of SIRT6 deacetylase from medicinal plant extracts. Anal Chem 83:7400-7 |
