缺乏ALT的細(xì)胞系(頂行)表明輻照誘導(dǎo)的DNA損傷24小時之后,，幾乎完全消失,。相反,，12個ALT細(xì)胞系(底行)中的11種在一天之后,，仍然保持著相當(dāng)大比例的輻照誘導(dǎo)的DNA損傷部位。
癌細(xì)胞是永生的,，這是因為它們能夠躲避阻止細(xì)胞不受控制增殖的故障保護(hù)機(jī)制(failsafe mechanism),。這些保護(hù)機(jī)制之一就是染色體的漸近性縮短，而癌細(xì)胞可以通過填補(bǔ)端粒---染色體末端的保護(hù)性序列--來阻止這種機(jī)制發(fā)揮作用,。大多數(shù)癌細(xì)胞是利用端粒酶來修復(fù)端粒的,，但是將近10%到15%的人類癌癥利用一種不同的被稱作端粒選擇性延長(alternative lengthening of telomere, ALT)的途徑來完成這一工作。腫瘤是否具有ALT差別非常大,。比如,，患有膠質(zhì)母細(xì)胞瘤(glioblastoma)的病人如果腫瘤具有ALT，那么他們存活的時間能夠提高2倍,。
來自美國洛克菲勒大學(xué),、麻省-哈佛布洛德研究所、斯隆-凱特琳癌癥中心癌癥紀(jì)念中心和威爾康乃爾醫(yī)學(xué)院的研究人員著手揭示ALT之謎,。研究人員詳細(xì)分析了很多ALT細(xì)胞系(即利用ALT來填補(bǔ)端粒的細(xì)胞系)的遺傳特征和細(xì)胞生物特征,。盡管人們一直不清楚ALT是如何被激活的，但是最近的研究數(shù)據(jù)指向一種被稱作ATRX的酶,。ATRX改變?nèi)旧w上DNA纏繞在蛋白上的方式,。
根據(jù)一項于2012年7月19日在線發(fā)表在PLoS Genetics期刊上的研究，研究人員發(fā)現(xiàn)在ALT細(xì)胞系的起源中,，ATRX缺失是一種常見的事件,。他們也證實ALT細(xì)胞系經(jīng)常性地經(jīng)歷染色體改變，同時它們檢測和修復(fù)DNA損傷的能力受到削弱,。
論文共同作者Titia de Lange教授說，“ALT的這些特征應(yīng)當(dāng)有助于在診所檢測ALT類型的腫瘤和可能導(dǎo)致人們開發(fā)出ALT特異性的治療方法,。它們可能也解釋了ALT腫瘤的差異性存活受益,。”(生物谷：Bioon.com)
本文編譯自Starr collaboration illuminates mysterious pathway to immortality in cancer cells
doi: 10.1371/journal.pgen.1002772
PMC:
PMID:
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
