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Molecular and Cellular Biology, July 1999, p. 4935-4943, Vol. 19, No. 7
Department of Biochemistry and Molecular
Biology, University of Illinois at Chicago, Chicago, Illinois
606121; Division of Biochemistry and
Molecular Biology, University of California, Berkeley, California
94720-32022; and Division of
Molecular Virology, Baylor College of Medicine, Houston, Texas
770303
Received 25 February 1999/Returned for modification 24 March
1999/Accepted 23 April 1999
The human UV-damaged-DNA binding protein DDB has been linked to the
repair deficiency disease xeroderma pigmentosum group E (XP-E), because
a subset of XP-E patients lack the damaged-DNA binding function of DDB.
Moreover, the microinjection of purified DDB complements the repair
deficiency in XP-E cells lacking DDB. Two naturally occurring XP-E
mutations of DDB, 82TO and 2RO, have been characterized. They have
single amino acid substitutions (K244E and R273H) within the WD motif
of the p48 subunit of DDB, and the mutated proteins lack the
damaged-DNA binding activity. In this report, we describe a new
function of the p48 subunit of DDB, which reveals additional defects in
the function of the XP-E mutants. We show that when the subunits of DDB
were expressed individually, p48 localized in the nucleus and p125
localized in the cytoplasm. The coexpression of p125 with p48 resulted
in an increased accumulation of p125 in the nucleus, indicating that p48 plays a critical role in the nuclear localization of p125. The
mutant forms of p48, 2RO and 82TO, are deficient in stimulating the
nuclear accumulation of the p125 subunit of DDB. In addition, the
mutant 2RO fails to form a stable complex with the p125 subunit of DDB.
Our previous studies indicated that DDB can associate with the
transcription factor E2F1 and can function as a transcriptional partner
of E2F1. Here we show that the two mutants, while they associate with
E2F1 as efficiently as wild-type p48, are severely impaired in
stimulating E2F1-activated transcription. This is consistent with our
observation that both subunits of DDB are required to stimulate
E2F1-activated transcription. The results provide insights into the
functions of the subunits of DDB and suggest a possible link between
the role of DDB in E2F1-activated transcription and the repair
deficiency disease XP-E.
0270-7306/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.
The Naturally Occurring Mutants of DDB Are Impaired
in Stimulating Nuclear Import of the p125 Subunit and
E2F1-Activated Transcription

*
Corresponding author. Mailing address: Department of
Biochemistry and Molecular Biology (M/C 536), University of Illinois at
Chicago, 1819 W. Polk St., Chicago, IL 60612. Phone: (312) 413-0255. Fax: (312) 413-0364. E-mail: Pradip{at}uic.edu.
Present address: Department of Biological Sciences, University of
Nevada, Las Vegas, Las Vegas, NV 89154.
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