Department of Cell and Molecular Biology, Karolinska Institute, Stockholm, Sweden.
Oncogene. 2013 Dec 5;32(49):5522-30. doi: 10.1038/onc.2013.189. Epub 2013 May 27.
Malignant cells achieve replicative immortality by two alternative mechanisms, a common one dependent on de novo synthesis of telomeric DNA by telomerase, and a rare one based on telomere recombination known as alternative lengthening of telomeres (ALT). Epstein-Barr virus (EBV) transforms human B-lymphocytes into lymphoblastoid cell lines with unlimited growth potential in vitro and in vivo. Here we show that newly EBV-infected cells exhibit multiple signs of telomere dysfunction, including the occurrence of extra-chromosomal telomeres, telomere fusion and telomere length heterogeneity, and undergo progressive increase in telomere length without a parallel increase in telomerase activity. This phenotype is accompanied by the accumulation of telomere-associated promyelocytic leukemia nuclear bodies and telomeric-sister chromatid exchange, suggesting that EBV infection promotes the activation of ALT. Newly infected cells also display a significant reduction of telomere-associated TRF2 and express low levels of TRF1, TRF2, POT1 and ATRX, pointing to telomere de-protection as an important correlate of ALT activation. Collectively, these findings highlight the involvement of recombination-dependent mechanisms for maintenance of telomere homeostasis in EBV-induced B-cell immortalization.
恶性细胞通过两种替代机制实现复制性永生，一种常见的机制依赖于端粒酶从头合成端粒 DNA，另一种罕见的机制依赖于端粒重组，称为端粒的替代性延长（ALT）。EB 病毒（EBV）将人类 B 淋巴细胞转化为体外和体内具有无限生长潜力的淋巴母细胞系。在这里，我们表明新感染 EBV 的细胞表现出多种端粒功能障碍的迹象，包括染色体外端粒的发生、端粒融合和端粒长度异质性，并且在端粒酶活性没有平行增加的情况下，端粒长度逐渐增加。这种表型伴随着端粒相关早幼粒细胞白血病核体的积累和端粒姐妹染色单体交换，表明 EBV 感染促进了 ALT 的激活。新感染的细胞还显示出端粒相关 TRF2 的显著减少，并表达低水平的 TRF1、TRF2、POT1 和 ATRX，表明端粒去保护是 ALT 激活的一个重要相关因素。总的来说，这些发现强调了在 EBV 诱导的 B 细胞永生化中，依赖于重组的机制在维持端粒稳态方面的参与。
