Sirt1 physically interacts with Tip60 and negatively regulates Tip60-mediated acetylation of H2AX.
Sirt1 appear to be NAD(+)-dependent deacetylase that deacetylates histones and several non-histone proteins. In this study, we identified Sirt1 as a physical interaction partner of Tip60, which is a mammalian MYST-type histone acetyl-transferase that specifically acetylates histones H2A and H4. Although Tip60 also acetylates DNA damage-specific histone H2A variant H2AX in response to DNA damage, which is a process required for appropriate DNA damage response, overexpression of Sirt1 represses Tip60-mediated acetylation of H2AX. Furthermore, Sirt1 depletion by RNAi causes excessive acetylation of H2AX, and enhances accumulation of gamma-ray irradiation-induced MDC1, BRCA1, and Rad51 foci in nuclei. These findings suggest that Sirt1 functions as negative regulator of Tip60-mediated acetylation of H2AX. Moreover, Sirt1 deacetylates an acetylated Tip60 in response to DNA damage and stimulates proteasome-dependent Tip60 degradation in vivo, suggesting that Sirt1 negatively regulates the protein level of Tip60 in vivo. Sirt1 may thus repress excessive activation of the DNA damage response and Rad51-homologous recombination repair by suppressing the function of Tip60.
Yamagata
Kazutsune
K
Department of Molecular Oncology Division, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan. kyamagat@ncc.go.jp
Kitabayashi
Issay
I
D000107:Acetylation; D002460:Cell Line; D004249:DNA Damage; D004260:DNA Repair; D017353:Gene Deletion; D051548:Histone Acetyltransferases / Q000378:metabolism*; D006657:Histones / Q000378:metabolism*; D006801:Humans; D008239:Lysine / Q000378:metabolism; D000074443:Lysine Acetyltransferase 5; D051135:Rad51 Recombinase / Q000378:metabolism; D056564:Sirtuin 1 / Q000235:genetics / Q000378:metabolism*
C468783:H2AX protein, human; D006657:Histones; D051548:Histone Acetyltransferases; C098489:KAT5 protein, human; D000074443:Lysine Acetyltransferase 5; D051135:Rad51 Recombinase; C447939:SIRT1 protein, human; D056564:Sirtuin 1; D008239:Lysine