Human Molecular Genetics Advance Access originally published online on January 30, 2006
Human Molecular Genetics 2006 15(6):831-838; doi:10.1093/hmg/ddl002
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A role for Brca1 in chromosome end maintenance
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1Advanced Medical Discovery Institute and 2Ontario Cancer Institute, Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada M5G 2C1, 3Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597, Singapore and 4Oncology Research Institute, National University Medical Institutes, Singapore 117597, Singapore
* To whom correspondence should be addressed at: Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Block MD9, 2 Medical Drive, Singapore 117597, Singapore. Tel: +65 65163664; Fax: +65 67788161; Email: phsmph{at}nus.edu.sg
Received December 7, 2005; Accepted January 21, 2006
The role of BRCA1 in breast and ovarian tumor suppression has been primarily ascribed to the maintenance of genome integrity. BRCA1 interacts with components of the non-homologous end-joining pathway previously shown to play a role in telomere maintenance in yeast. Here, we provide evidence that links Brca1 with telomere integrity. Brca1–/– T-cells display telomere dysfunction in both loss of telomere repeats as well as defective telomere capping. Loss of Brca1 synergizes with p53 deficiency in the onset and frequency of tumorigenesis. Karyotyping of tBrca1–/–p53–/– thymic lymphomas revealed the presence of telomere dysfunction accompanied by clonal chromosomal translocations. The telomere dysfunction phenotype in Brca1-deficient cells suggests that loss of telomere integrity might contribute to chromosome end dysfunction and permit the formation of potentially oncogenic translocations.
The authors wish it to be known that, in their opinion, the first two authors should be regarded as joint First Authors.
Present Address: Department of Pharmacology, University of Toronto, Toronto, Ontario, Canada M5S 1A8.
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