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First published online 16 September 2003
doi: 10.1242/jcs.00747
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Research Article |
1 Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA
2 Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02115, USA
3 Department of Pathology, Harvard Medical School, Boston, MA 02115, USA
4 Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, Boston, MA 02115, USA
* Author for correspondence (e-mail: pamela_silver{at}dfci.harvard.edu)
Accepted 7 July 2003
The human immunodeficiency virus type 1 integrase protein has karyophilic properties; that is, it localizes to the cell nucleus according to a range of assays. As an essential component of the preintegration complex, it has been suggested that the karyophilic properties of integrase might facilitate transport of the preintegration complex through the nuclear pore complexes of nondividing cells. However, no experiments have satisfactorily identified a nuclear localization signal within integrase. In this work, we investigated the karyophilic properties of integrase in intact cells with hopes of identifying a genuine transferable nuclear localization signal. Our results confirm that integrase tightly binds chromosomal DNA in vivo. However, our analysis determined that large integrase fusion proteins are unable to access the nucleus, indicating that integrase might lack a transferable nuclear localization signal. In addition, we present several lines of evidence to indicate that DNA binding might facilitate integrase nuclear accumulation. Furthermore, our data indicate integrase is degraded in the cytoplasm by a proteasome-dependent process, an event that probably contributes to the apparent nuclear accumulation of integrase. These results provide new insight into human immunodeficiency virus type 1 integrase intracellular dynamics.
Key words: HIV-1, Integrase, Nuclear transport, Preintegration complex
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