Role of NAD-dependent deacetylases SIRT1 and SIRT2 in radiation and cisplatin-induced cell death in vertebrate cells.
Yeast Sir2 is a nicotinamide adenine dinucleotide (NAD)-dependent histone deacetylase that plays a central role in transcriptional silencing, chromosomal stability, DNA damage response and aging. In mammals, Sir2-like genes constitute a seven-member family whose function is largely unknown. To investigate the role of the Sir2 family in vertebrates, we have disrupted Sir2 homologues SIRT1 and SIRT2 in the p53-deficient chicken cell line DT40. Both SIRT1-/- and SIRT2-/- cells had mild growth defects. Colony survival assays showed moderate and mild sensitivity to cisplatin in SIRT1-/- and SIRT2-/- cells, respectively, while SIRT1-/-, but not SIRT2-/- cells, were sensitive to ionizing radiation (IR). Cells rendered doubly deficient in SIRT1 and SIRT2 exhibited the same levels of IR and cisplatin sensitivity as SIRT1-/- cells. SIRT1-/- cells appeared to be defective neither in DNA double strand break repair nor in G2/M checkpoints, but were more susceptible to cell death induction following IR than wild-type cells. Furthermore, both SIRT1- and SIRT2-deficient cells were more sensitive to pro-apoptotic stimuli including cisplatin and staurosporine. Our results indicate that SIRT1 and SIRT2 regulate stress-induced cell death pathways in a p53-independent manner.[1]References
- Role of NAD-dependent deacetylases SIRT1 and SIRT2 in radiation and cisplatin-induced cell death in vertebrate cells. Matsushita, N., Takami, Y., Kimura, M., Tachiiri, S., Ishiai, M., Nakayama, T., Takata, M. Genes Cells (2005) [Pubmed]
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