缺乏ALT的细胞系(顶行)表明辐照诱导的DNA损伤24小时之后，几乎完全消失。相反，12个ALT细胞系(底行)中的11种在一天之后，仍然保持着相当大比例的辐照诱导的DNA损伤部位。
癌细胞是永生的，这是因为它们能够躲避阻止细胞不受控制增殖的故障保护机制(failsafe mechanism)。这些保护机制之一就是染色体的渐近性缩短，而癌细胞可以通过填补端粒---染色体末端的保护性序列--来阻止这种机制发挥作用。大多数癌细胞是利用端粒酶来修复端粒的，但是将近10%到15%的人类癌症利用一种不同的被称作端粒选择性延长(alternative lengthening of telomere, ALT)的途径来完成这一工作。肿瘤是否具有ALT差别非常大。比如，患有胶质母细胞瘤(glioblastoma)的病人如果肿瘤具有ALT，那么他们存活的时间能够提高2倍。
来自美国洛克菲勒大学、麻省-哈佛布洛德研究所、斯隆-凯特琳癌症中心癌症纪念中心和威尔康乃尔医学院的研究人员着手揭示ALT之谜。研究人员详细分析了很多ALT细胞系(即利用ALT来填补端粒的细胞系)的遗传特征和细胞生物特征。尽管人们一直不清楚ALT是如何被激活的，但是最近的研究数据指向一种被称作ATRX的酶。ATRX改变染色体上DNA缠绕在蛋白上的方式。
根据一项于2012年7月19日在线发表在PLoS Genetics期刊上的研究，研究人员发现在ALT细胞系的起源中，ATRX缺失是一种常见的事件。他们也证实ALT细胞系经常性地经历染色体改变，同时它们检测和修复DNA损伤的能力受到削弱。
论文共同作者Titia de Lange教授说，“ALT的这些特征应当有助于在诊所检测ALT类型的肿瘤和可能导致人们开发出ALT特异性的治疗方法。它们可能也解释了ALT肿瘤的差异性存活受益。”(生物谷：Bioon.com)
本文编译自Starr collaboration illuminates mysterious pathway to immortality in cancer cells
doi: 10.1371/journal.pgen.1002772
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Loss of ATRX, Genome Instability, and an Altered DNA Damage Response Are Hallmarks of the Alternative Lengthening of Telomeres Pathway
Courtney A. Lovejoy1, Wendi Li1, Steven Reisenweber1, Supawat Thongthip1, Joanne Bruno1, Titia de Lange1*, Saurav De2, John H. J. Petrini2, Patricia A. Sung et al.
The Alternative Lengthening of Telomeres (ALT) pathway is a telomerase-independent pathway for telomere maintenance that is active in a significant subset of human cancers and in vitro immortalized cell lines. ALT is thought to involve templated extension of telomeres through homologous recombination, but the genetic or epigenetic changes that unleash ALT are not known. Recently, mutations in the ATRX/DAXX chromatin remodeling complex and histone H3.3 were found to correlate with features of ALT in pancreatic neuroendocrine cancers, pediatric glioblastomas, and other tumors of the central nervous system, suggesting that these mutations might contribute to the activation of the ALT pathway in these cancers. We have taken a comprehensive approach to deciphering ALT by applying genomic, molecular biological, and cell biological approaches to a panel of 22 ALT cell lines, including cell lines derived in vitro. Here we show that loss of ATRX protein and mutations in the ATRX gene are hallmarks of ALT–immortalized cell lines. In addition, ALT is associated with extensive genome rearrangements, marked micronucleation, defects in the G2/M checkpoint, and altered double-strand break (DSB) repair. These attributes will facilitate the diagnosis and treatment of ALT positive human cancers
