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Molecular and Cellular Biology, June 2001, p. 4005-4015, Vol. 21, No. 12
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

L. Julie Huber,1 Thomas W. Yang,1 Christopher J. Sarkisian,1 Stephen R. Master,1 Chu-Xia Deng,2 and Lewis A. Chodosh1,3,*

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-Delta 11, which lacks exon 11 in its entirety, including putative nuclear localization signals. Consistent with this, BRCA1-Delta 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-Delta 11 localizes to discrete nuclear foci indistinguishable from those found in wild-type cells, despite the fact that Brca1-Delta 11 lacks previously defined nuclear localization signals. However, we further show that DNA damage-induced phosphorylation of Brca1-Delta 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-Delta 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-Delta 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.

Molecular and Cellular Biology, June 2001, p. 4005-4015, Vol. 21, No. 12
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.12.4005-4015.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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