Chromosomal aberrations involving telomeres in BRCA1 deficient human and mouse cell lines.
Cells defective in BRCA1 show genomic instability as evidenced by increased radiosensitivity, the presence of chromosomal abnormalities and the loss of heterozygosity at many loci. Reported chromosomal abnormalities in BRCA1 deficient cells include dicentric chromosomes. Dicentric chromosomes, in some cases, may arise as a result of end-to-end chromosome fusions, which represent signatures of telomere dysfunction. In this study we examined BRCA1 deficient human and mouse cells for the presence of chromosomal aberrations indicative of telomere dysfunction. We identified a lymphoblastoid cell line, GM14090, established from a BRCA1 carrier that showed elevated levels of dicentric chromosomes. Molecular cytogenetic analysis revealed that these dicentric chromosomes result from end-to-end chromosome fusions. The frequency of end-to-end chromosome fusions did not change after exposure of GM14090 cells to bleomycin but we observed elevated levels of chromosomal abnormalities involving interactions between DNA double strand breaks and uncapped telomeres in this cell line. We observed similar chromosomal abnormalities involving telomeres in the breast cancer cell line, HCC1937, homozygous for BRCA1 mutation. Finally, we analyzed mouse embryonic stem cells lacking functional Brca1 and observed the presence of telomere dysfunction following exposure of these cells to bleomycin. Our results reveal cytogenetic evidence of telomere dysfunction in BRCA1 deficient cells.
Al-Wahiby
S
S
Brunel Institute of Cancer Genetics and Pharmacogenomics, Department of Biological Sciences, Brunel University, Uxbridge, UK.
Slijepcevic
P
P
D000818:Animals; D019313:BRCA1 Protein / Q000172:deficiency* / Q000235:genetics; D001761:Bleomycin / Q000494:pharmacology; D001943:Breast Neoplasms / Q000201:enzymology / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D045744:Cell Line, Tumor; D002869:Chromosome Aberrations; D020732:Cytogenetic Analysis; D004622:Embryo, Mammalian / Q000166:cytology; D004847:Epithelial Cells / Q000737:chemistry / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D006801:Humans; D017404:In Situ Hybridization, Fluorescence / Q000379:methods; D008214:Lymphocytes / Q000737:chemistry / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D008677:Metaphase / Q000235:genetics; D051379:Mice; D009154:Mutation / Q000235:genetics; D013234:Stem Cells / Q000737:chemistry / Q000378:metabolism; D019098:Telomerase / Q000378:metabolism; D016615:Telomere / Q000235:genetics*
D019313:BRCA1 Protein; D001761:Bleomycin; D019098:Telomerase