A role for Brca1 in chromosome end maintenance.
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.
McPherson
J Peter
JP
Advanced Medical Discovery Institute, Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada M5G 2C1. phsmph@nus.edu.sg
Hande
M Prakash
MP
Poonepalli
Anuradha
A
Lemmers
Benedicte
B
Zablocki
Elzbieta
E
Migon
Eva
E
Shehabeldin
Amro
A
Porras
Annaliza
A
Karaskova
Jana
J
Vukovic
Bisera
B
Squire
Jeremy
J
Hakem
Razqallah
R
D000818:Animals; D019313:BRCA1 Protein / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D017404:In Situ Hybridization, Fluorescence; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D010641:Phenotype; D011518:Proto-Oncogene Proteins / Q000235:genetics; D019253:Proto-Oncogene Proteins c-bcl-2; D013601:T-Lymphocytes / Q000378:metabolism / Q000473:pathology; D016615:Telomere / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D013945:Thymoma / Q000235:genetics / Q000473:pathology; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency / Q000235:genetics
D019313:BRCA1 Protein; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D016159:Tumor Suppressor Protein p53; C052617:Bcl2 protein, mouse