Al-Wahiby S, Slijepcevic P
Brunel Institute of Cancer Genetics and Pharmacogenomics, Department of Biological Sciences, Brunel University, Uxbridge, UK.
Cytogenet Genome Res. 2005;109(4):491-6. doi: 10.1159/000084208.
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.
BRCA1有缺陷的细胞表现出基因组不稳定，这可通过放射敏感性增加、染色体异常的存在以及许多位点杂合性的丧失得到证明。在BRCA1缺陷细胞中报道的染色体异常包括双着丝粒染色体。在某些情况下，双着丝粒染色体可能是由于端到端染色体融合产生的，这代表了端粒功能障碍的特征。在本研究中，我们检查了BRCA1缺陷的人类和小鼠细胞中是否存在表明端粒功能障碍的染色体畸变。我们鉴定出一种从BRCA1携带者建立的淋巴母细胞系GM14090，其双着丝粒染色体水平升高。分子细胞遗传学分析表明，这些双着丝粒染色体是由端到端染色体融合产生的。GM14090细胞暴露于博来霉素后，端到端染色体融合的频率没有改变，但我们观察到该细胞系中涉及DNA双链断裂与无帽端粒相互作用的染色体异常水平升高。我们在BRCA1突变纯合子的乳腺癌细胞系HCC1937中观察到了类似的涉及端粒的染色体异常。最后，我们分析了缺乏功能性Brca1的小鼠胚胎干细胞，并观察到这些细胞暴露于博来霉素后存在端粒功能障碍。我们的结果揭示了BRCA1缺陷细胞中端粒功能障碍的细胞遗传学证据。
