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.
Matsushita
Nobuko
N
Department of Immunology and Molecular Genetics, Kawasaki Medical School, 577 Matsushima, Kurashiki, Okayama 701-0192, Japan.
Takami
Yasunari
Y
Kimura
Masayo
M
Tachiiri
Seiji
S
Ishiai
Masamichi
M
Nakayama
Takeo
T
Takata
Minoru
M
D000818:Animals; D002453:Cell Cycle / Q000187:drug effects / Q000528:radiation effects; D016923:Cell Death; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects / Q000528:radiation effects; D002645:Chickens; D002869:Chromosome Aberrations / Q000528:radiation effects; D002945:Cisplatin / Q000494:pharmacology*; D004249:DNA Damage; D004260:DNA Repair / Q000187:drug effects / Q000528:radiation effects; D037761:Sirtuins / Q000235:genetics / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics; D014466:Ultraviolet Rays; D014965:X-Rays
D016159:Tumor Suppressor Protein p53; D037761:Sirtuins; D002945:Cisplatin