Among mammalian histone deacetylases (HDACs) identified so far, HDAC6 is unique in that it possesses tandem deacetylase domains, as well as a carboxyl-terminal zinc finger motif implicated in ubiquitin binding. HDAC6 has also been demonstrated to deacetylate tubulin and thus potentially contribute to regulation of cell motility. Although HDAC6 has been reported to interact with a variety of nuclear factors, this enzyme is predominantly localized to the cytoplasm. / Here I show that the subcellular localization of human HDAC6 is governed by additional elements not present in orthologues of this protein from other species. Human HDAC6 contains a unique insertion of eight or ten repeats of a Ser/Glu-containing tetradecapeptide sequence, here termed the SE14-repeat domain, which is responsible for mediating the Leptomycin B-resistant cytoplasmic retention of human HDAC6. Human HDAC6 also contains a second functional leucine-rich nuclear export signal when compared to murine HDAC6, and a region near the amino terminus of human HDAC6 is capable of mediating nuclear import. / I have also identified a previously uncharacterized protein containing a ubiquitin-like domain, here termed Ubl90, as a novel binding partner for HDAC6. Interestingly, Ubl90 binds to the deacetylase domains of HDAC6, rather than to the carboxyl-terminal zinc finger motif previously implicated in ubiquitin association. Ubl90 also interacts with several class I HDACs (HDAC1, HDAC2 and HDAC8), although more weakly than with HDAC6. When Ubl90 is overexpressed, it leads to the redistribution of HDAC1 from a nuclear to a pancellular localization, although this does not affect HDAC1-dependent transcriptional repression in a transient transfection assay. Like HDAC6, Ubl90 is capable of repressing Runx2-mediated transcriptional activation, and, when overexpressed, it leads to cell cycle disturbances similar to those seen with HDAC6 overexpression. These results suggest that Ubl90 and HDAC6 interact functionally, as well as physically.
| Identifer | oai:union.ndltd.org:LACETR/oai:collectionscanada.gc.ca:QMM.84474 |
| Date | January 2004 |
| Creators | Bertos, Nicholas R. |
| Contributors | Yang, Xiang-Jio (advisor), Dhindsa, Rajinder S. (advisor) |
| Publisher | McGill University |
| Source Sets | Library and Archives Canada ETDs Repository / Centre d'archives des thèses électroniques de Bibliothèque et Archives Canada |
| Language | English |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Format | application/pdf |
| Coverage | Doctor of Philosophy (Department of Biology.) |
| Rights | All items in eScholarship@McGill are protected by copyright with all rights reserved unless otherwise indicated. |
| Relation | alephsysno: 002150396, proquestno: AAINQ98207, Theses scanned by UMI/ProQuest. |
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