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Molecular and Cellular Biology, June 2001, p. 4005-4015, Vol. 21, No. 12
Department of Molecular & Cellular
Engineering1 and Division of
Endocrinology, Diabetes and Metabolism,3
University of Pennsylvania School of Medicine, Philadelphia,
Pennsylvania 19104-6160, and Genetics of Development and
Disease Branch, National Institute of Diabetes, Digestive, and Kidney
Diseases, National Institutes of Health, Bethesda, Maryland
208922
Received 7 September 2000/Returned for modification 23 October
2000/Accepted 27 March 2001
Both human and mouse cells express an alternatively spliced variant
of BRCA1, BRCA1-
0270-7306/01/$04.00+0 DOI: 10.1128/MCB.21.12.4005-4015.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.
Impaired DNA Damage Response in Cells Expressing
an Exon 11-Deleted Murine Brca1 Variant That Localizes to
Nuclear Foci
11, which lacks exon 11 in its entirety, including
putative nuclear localization signals. Consistent with this,
BRCA1-
11 has been reported to reside in the cytoplasm, a
localization that would ostensibly preclude it from playing a role in
the nuclear processes in which its full-length counterpart has been
implicated. Nevertheless, the finding that murine embryos bearing
homozygous deletions of exon 11 survive longer than embryos that are
homozygous for Brca1 null alleles suggests that exon 11-deleted isoforms may perform at least some of the functions of
Brca1. We have analyzed both the full-length and the exon 11-deleted isoforms of the murine Brca1 protein. Our results demonstrate that
full-length murine Brca1 is identical to human BRCA1 with respect to
its cell cycle regulation, DNA damage-induced phosphorylation, nuclear
localization, and association with Rad51. Surprisingly, we show that
endogenous Brca1-
11 localizes to discrete nuclear foci
indistinguishable from those found in wild-type cells, despite the fact
that Brca1-
11 lacks previously defined nuclear localization signals.
However, we further show that DNA damage-induced phosphorylation of
Brca1-
11 is significantly reduced compared to full-length Brca1, and
that gamma irradiation-induced Rad51 focus formation is impaired in
cells in which only Brca1-
11 is expressed. Our results suggest that
the increased viability of embryos bearing homozygous deletions of exon
11 may be due to expression of Brca1-
11 and suggest an explanation
for the genomic instability that accompanies the loss of full-length Brca1.
*
Corresponding author. Mailing address: Dept. of
Molecular and Cellular Engineering, 612 Biomedical Res. Bldg II/III,
University of Pennsylvania School of Medicine, 421 Curie Blvd.,
Philadelphia, PA 19104-6160. Phone: (215) 898-1321. Fax: (215)
573-6725. E-mail: chodosh{at}mail.med.upenn.edu.
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