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doi: 10.1242/10.1242/dev.00410
DEVELOPMENT AND DISEASE |
1 Department of Physiology, University of Maryland School of Medicine, Baltimore
21201, USA
2 Genetics of Development and Disease Branch, 10/9N105, National Institute of
Diabetes and Digestive and Kidney Diseases, National Institutes of Health,
Bethesda, MD 20892, USA
3 Laboratory of Biosystems and Cancer, 37/5016, Center for Cancer Research,
National Cancer Institute, National Institutes of Health, Bethesda, MD 20892,
USA
4 Department of Biology, York University, Toronto, Ontario, M3J 1P3,
Canada
5 Department of Oncology, Lombardi Cancer Center, Georgetown University Medical
Center, Washington, DC 20007, USA
* Author for correspondence (e-mail: xiaolingx{at}intra.niddk.nih.gov)
Accepted 24 January 2003
Breast tumor suppressor gene 1 (BRCA1) plays an essential role in
maintaining genomic integrity. Here we show that mouse Brca1 is
required for DNA-damage repair and crossing-over during spermatogenesis. Male
Brca1
11/11p53+/- mice that
carried a homozygous deletion of Brca1 exon 11 and a p53
heterozygous mutation had significantly reduced testicular size and no
spermatozoa in their seminiferous tubules. During spermatogenesis, homologous
chromosomes from the mutant mice synapsed and advanced to the pachytene stage
but failed to progress to the diplotene stage. Our analyses revealed that the
Brca1 mutation affected cellular localization of several DNA
damage-repair proteins. This included prolonged association of 
H2AX
with sites of DNA damage, reduced sex body formation, diminished Rad51 foci
and absence of Mlh1 foci in the pachytene stage. Consequently, chromosomes
from mutant mice did not form chiasmata, a point that connects exchanging
homologous chromosomes. Brca1-mutant spermatocytes also exhibited
decreased RNA expression levels of several genes that are involved in
DNA-damage repair, including RuvB-like DNA helicase, XPB, p62 and TFIID. Of
note, the premature termination of spermatogenesis at the pachytene stage was
accompanied by increased apoptosis by both p53-dependent and p53-independent
mechanisms. Thus, our study revealed an essential role of Brca1 in DNA-damage
repair and crossing-over of homologous chromosomes during spermatogenesis.
Key words: BRCA1, MLH1, H2AX, Crossing-over, Apoptosis
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