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EMBO reports 7, 12, 1247–1251 (2006)
doi:10.1038/sj.embor.7400829
AOP Published online: 17 November 2006
Nuclear export modulates the cytoplasmic Sir2 homologue Hst2
Jeanne M Wilson1, Viet Q Le1, Collin Zimmerman1, Ronen Marmorstein2 & Lorraine Pillus1, 3
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1 Division of Biological Sciences, Section of Molecular Biology, University of California, San Diego, 9500 Gilman Drive, 0347, La Jolla, California 92093, USA
2 The Wistar Institute and Department of Chemistry, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA
3 UCSD Cancer Center, University of California, San Diego, 9500 Gilman Drive, 0347, La Jolla, California 92093, USA
To whom correspondence should be addressed
Lorraine Pillus Tel: +1 858 822 2442; Fax: +1 858 534 0555; E-mail: lpillus@ucsd.edu
Received 20 March 2006; Accepted 13 September 2006; Published online 17 November 2006.
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Abstract
Modulating transcription factors is crucial to executing sophisticated gene expression programs. The silent information regulator 2 (Sir2) family of NAD-dependent protein deacetylases influences transcription by targeting proteins such as histones, p53 and forkhead-box family transcription factors. Although apparently cytoplasmic, both mammalian SIRT2 and its yeast orthologue Hst2 have been implicated in transcriptional regulation. Here, we show that Hst2 moves between the nucleus and cytoplasm, but is largely cytoplasmic owing to efficient nuclear export. This nuclear exclusion is mediated by the exportin chromosomal region maintenance 1 (Crm1) and a putative leucine-rich nuclear export sequence in Hst2, which overlaps a unique autoregulatory helix. Disruption of Hst2 export shows that nuclear exclusion inhibits the activity of Hst2 as a transcriptional repressor. Our identification of putative nuclear export sequences in numerous vertebrate SIRT2 proteins shows that active nuclear export can be a conserved mechanism for regulating Sir2 homologues.
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