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腾讯登录Cell：揭示癌细胞永生的秘密
| 导读 | 近日，刊登在国际杂志Cell上的一篇研究论文中，来自宾夕法尼亚大学的研究人员通过研究揭示了为何癌细胞可以维持端粒的功能而得以永生。 |
维持染色体端粒的功能是细胞进行持续分裂的关键，当然端粒也是人类癌症发生的标志；端粒就好比是携带末端的塑料帽一样，其可以阻止DNA末端被不断“磨损”；近日，刊登在国际杂志Cell上的一篇研究论文中，来自宾夕法尼亚大学的研究人员通过研究揭示了为何癌细胞可以维持端粒的功能而得以永生。
在许多癌细胞中端粒都是完好无损的，因为癌细胞可以利用特殊的端粒酶来不断往染色体末端添加端粒DNA序列，当然癌细胞同时也会使用第二种涉及DNA修复机制的方式，名为端粒的替代延长(ALT)技术；一般来讲，癌细胞可以维持端粒机器使其发挥正常功能从而不断增殖，总的来讲，大约15%的癌细胞都可以利用ALT机制来延长端粒的长度。这项研究中，研究小组揭示，当DNA破碎时，其会诱发DNA修复蛋白活化，就好比乳腺癌抑制蛋白BRCA2一样，DNA修复蛋白会在其它“助手”蛋白的帮助下吸附到损伤的DNA上，随后修复蛋白在DNA链上伸展，使其可以搜寻到端粒DNA的互补序列，乳腺癌往往和BRCA1和BRCA2基因突变相关，而涉及BRCA相关途径的突变往往和乳腺癌的易感性相关。
研究者Greenberg指出，乳腺癌和卵巢癌都是和BRCA介导的DNA修复系统的破坏相关，修复过程会引发端粒的移动和聚集，破碎的端粒会利用同源性的端粒作为模板来进行自我修复；实际上，研究者可以对癌细胞利用ALT机制来维持端粒功能的整个过程进行清楚地解析。
本文的研究数据对于揭示端粒维持的机制及理解癌症的发生根源提供了很详尽的参考依据，为下一步开发新型小分子药物来靶向作用癌细胞带来了极大的帮助。（转化医学网360zhyx.com）
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转化医学网推荐的原文摘要：
Interchromosomal Homology Searches Drive Directional ALT Telomere Movement and Synapsis
Cell DOI: http://dx.doi.org/10.1016/j.cell.2014.08.030
Nam Woo Cho, Robert L. Dilley, Michael A. Lampson, Roger A. Greenberg
Telomere length maintenance is a requisite feature of cellular immortalization and a hallmark of human cancer. While most human cancers express telomerase activity, ∼10%–15% employ a recombination-dependent telomere maintenance pathway known as alternative lengthening of telomeres (ALT) that is characterized by multitelomere clusters and associated promyelocytic leukemia protein bodies. Here, we show that a DNA double-strand break (DSB) response at ALT telomeres triggers long-range movement and clustering between chromosome termini, resulting in homology-directed telomere synthesis. Damaged telomeres initiate increased random surveillance of nuclear space before displaying rapid directional movement and association with recipient telomeres over micron-range distances. This phenomenon required Rad51 and the Hop2-Mnd1 heterodimer, which are essential for homologous chromosome synapsis during meiosis. These findings implicate a specialized homology searching mechanism in ALT-dependent telomere maintenance and provide a molecular basis underlying the preference for recombination between nonsister telomeres during ALT.
Cell DOI: http://dx.doi.org/10.1016/j.cell.2014.08.030
Nam Woo Cho, Robert L. Dilley, Michael A. Lampson, Roger A. Greenberg
Telomere length maintenance is a requisite feature of cellular immortalization and a hallmark of human cancer. While most human cancers express telomerase activity, ∼10%–15% employ a recombination-dependent telomere maintenance pathway known as alternative lengthening of telomeres (ALT) that is characterized by multitelomere clusters and associated promyelocytic leukemia protein bodies. Here, we show that a DNA double-strand break (DSB) response at ALT telomeres triggers long-range movement and clustering between chromosome termini, resulting in homology-directed telomere synthesis. Damaged telomeres initiate increased random surveillance of nuclear space before displaying rapid directional movement and association with recipient telomeres over micron-range distances. This phenomenon required Rad51 and the Hop2-Mnd1 heterodimer, which are essential for homologous chromosome synapsis during meiosis. These findings implicate a specialized homology searching mechanism in ALT-dependent telomere maintenance and provide a molecular basis underlying the preference for recombination between nonsister telomeres during ALT.
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