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SirT3 is a nuclear NAD⁺-dependent histone deacetylase that translocates to the mitochondria upon cellular stress

¹ Howard Hughes Medical Institute, New York University Medical School, New York, New York 10016, USA; ² Department of Biochemistry, New York University Medical School, New York, New York 10016, USA; ³ Department of Biochemistry, Division of Nucleic Acids Enzymology, Robert Wood Johnson Medical School, University of Medicine and Dentistry of New Jersey, Piscataway, New Jersey 08854, USA

In humans, there are at least seven Sir2-like proteins (SirT1–7) with diverse functions, including the regulation of chromatin structure, and metabolism. SirT3 levels have been shown to correlate with extended life span, to localize to the mitochondria, and to be highly expressed in brown adipose tissue. In humans, SirT3 exists in two forms, a full-length protein of 44 kDa and a processed polypeptide lacking 142 amino acids at its N terminus. We found that SirT3 not only localizes to the mitochondria, but also to the nucleus under normal cell growth conditions. Both the full-length and processed forms of SirT3 target H4-K16 for deacetylation in vitro and can deacetylate H4-K16 in vivo when recruited to a gene. Using a highly specific antibody against the N terminus of SirT3, we found that SirT3 is transported from the nucleus to the mitochondria upon cellular stress. This includes DNA damage induced by Etoposide and UV-irradiation, as well as overexpression of SirT3 itself.

[Keywords: Histone deacetylation; chromatin; mitochondria; SirT3]

Received December 31, 2006; revised version accepted February 21, 2007.

⁵ Corresponding author.

E-MAIL reinbd01{at}med.nyu.edu; FAX (212) 263-9040.

Article is online at http://www.genesdev.org/cgi/doi/10.1101/gad.1527307

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