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Papers In Press, published online ahead of print July 31, 2002
Department of Genetics & Microbiology, C.M.U. / University of Geneva, Geneva CH-1211
Corresponding Author: Michel.Strubin{at}medecine.unige.ch
The hepatitis B virus X protein (HBx) is essential for viral infection and strongly interferes with cell growth and viability in culture. These activities involve interaction of HBx with the DDB1 subunit of UV-damaged DNA-binding factor UV-DDB. UV-DDB consists of DDB1 and a DDB2 subunit that mediates nuclear import, and has recognized functions in DNA repair and E2F1-mediated transcription. Here we show that HBx retains DDB1-binding-dependant cytotoxic activities when engineered to accumulate in the nucleus but not when excluded from the nucleus. Nuclear localization of HBx does not require binding to DDB1 and remains unaffected by ectopically expressed UV-DDB subunits, indicating that HBx reaches the nuclear compartment independently of UV-DDB. Unexpectedly, HBx appears to largely exist in association with DDB1 and is in direct competition with DDB2 for binding to DDB1. Hence, HBx-mediated cell death can be relieved by increased levels of DDB2, an effect that is not observed with a naturally occurring mutant of DDB2 that lacks DDB1-binding activity. These findings indicate that HBx acts through a pathway that involves a DDB2-independent nuclear function of DDB1, and that this activity will depend on the relative concentration of DDB1 and DDB2 in cells.
J. Biol. Chem, 10.1074/jbc.M205722200
Submitted on June 10, 2002
Revised on July 30, 2002
Accepted on July 30, 2002
HBx associated with UV-DDB1 induces cell death in the nucleus and is functionally antagonized by UV-DDB2
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