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Molecular and Cellular Biology, May 2003, p. 3173-3185, Vol. 23, No. 9
0270-7306/03/$08.00+0     DOI: 10.1128/MCB.23.9.3173-3185.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Role for Human SIRT2 NAD-Dependent Deacetylase Activity in Control of Mitotic Exit in the Cell Cycle

Sylvia C. Dryden, Fatimah A. Nahhas, James E. Nowak, Anton-Scott Goustin, and Michael A. Tainsky*

Program in Molecular Biology and Genetics, Karmanos Cancer Institute and Wayne State University, Detroit, Michigan 48201

Received 18 October 2002/ Returned for modification 7 January 2003/ Accepted 7 February 2003

Studies of yeast have shown that the SIR2 gene family is involved in chromatin structure, transcriptional silencing, DNA repair, and control of cellular life span. Our functional studies of human SIRT2, a homolog of the product of the yeast SIR2 gene, indicate that it plays a role in mitosis. The SIRT2 protein is a NAD-dependent deacetylase (NDAC), the abundance of which increases dramatically during mitosis and is multiply phosphorylated at the G2/M transition of the cell cycle. Cells stably overexpressing the wild-type SIRT2 but not missense mutants lacking NDAC activity show a marked prolongation of the mitotic phase of the cell cycle. Overexpression of the protein phosphatase CDC14B, but not its close homolog CDC14A, results in dephosphorylation of SIRT2 with a subsequent decrease in the abundance of SIRT2 protein. A CDC14B mutant defective in catalyzing dephosphorylation fails to change the phosphorylation status or abundance of SIRT2 protein. Addition of 26S proteasome inhibitors to human cells increases the abundance of SIRT2 protein, indicating that SIRT2 is targeted for degradation by the 26S proteasome. Our data suggest that human SIRT2 is part of a phosphorylation cascade in which SIRT2 is phosphorylated late in G2, during M, and into the period of cytokinesis. CDC14B may provoke exit from mitosis coincident with the loss of SIRT2 via ubiquitination and subsequent degradation by the 26S proteasome.

* Corresponding author. Mailing address: Program in Molecular Biology and Genetics, Karmanos Cancer Institute, 110 E. Warren, Prentis 311, Detroit, MI 48201-3917. Phone: (313) 833-0715, ext. 2641. Fax: (313) 832-7294. E-mail: tainskym{at}karmanos.org.

Molecular and Cellular Biology, May 2003, p. 3173-3185, Vol. 23, No. 9
0022-538X/03/$08.00+0     DOI: 10.1128/MCB.23.9.3173-3185.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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