Royle Nicola J, Méndez-Bermúdez Aarón, Gravani Athanasia, Novo Clara, Foxon Jenny, Williams Jonathan, Cotton Victoria, Hidalgo Alberto
Department of Genetics, University of Leicester, University Road, Leicester, UK.
Biochem Soc Trans. 2009 Jun;37(Pt 3):589-95. doi: 10.1042/BST0370589.
Human telomeres shorten during each cell division, predominantly because of incomplete DNA replication. This eventually results in short uncapped telomeres that elicit a DNA-damage response, leading to cellular senescence. However, evasion of senescence results in continued cell division and telomere erosion ultimately results in genome instability. In the long term, this genome instability is not sustainable, and cancer cells activate a TMM (telomere maintenance mechanism), either expression of telomerase or activation of the ALT (alternative lengthening of telomeres) pathway. Activation of the ALT mechanism results in deregulation of recombination-based activities at telomeres. Thus ALT+ cells show elevated T-SCE (telomere sister-chromatid exchange), misprocessing of t-loops that cap chromosomes and recombination-based processes between telomeres or between telomeres and ECTRs (extrachromosomal telomeric repeats). Some or all of these processes underlie the chaotic telomere length maintenance that allows cells in ALT+ tumours unlimited replicative capacity. ALT activation is also associated with destabilization of a minisatellite, MS32. The connection between the minisatellite instability and the deregulation of recombination-based activity at telomeres is not understood, but analysis of the minisatellite can be used as a marker for ALT. It is known that telomere length maintenance in ALT+ cells is dependent on the MRN [MRE11 (meiotic recombination 11)-Rad50-NBS1 (Nijmegen breakage syndrome 1)] complex, but knowledge of the role of other genes, including the Werner's (WRN) and Bloom's (BLM) syndrome DNA helicase genes, is still limited.
在每次细胞分裂过程中，人类端粒都会缩短，这主要是由于DNA复制不完全所致。这最终会导致产生短的无帽端粒，从而引发DNA损伤反应，进而导致细胞衰老。然而，逃避衰老会导致细胞持续分裂，端粒侵蚀最终会导致基因组不稳定。从长远来看，这种基因组不稳定是无法持续的，癌细胞会激活一种端粒维持机制（TMM），即端粒酶的表达或端粒替代延长（ALT）途径的激活。ALT机制的激活会导致端粒处基于重组的活动失调。因此，ALT+细胞表现出端粒姐妹染色单体交换（T-SCE）增加、染色体帽状t环的处理错误以及端粒之间或端粒与染色体外端粒重复序列（ECTR）之间基于重组的过程。这些过程中的一些或全部是ALT+肿瘤细胞中允许细胞具有无限复制能力的混乱端粒长度维持的基础。ALT激活还与一个小卫星MS32的不稳定有关。小卫星不稳定与端粒处基于重组的活动失调之间的联系尚不清楚，但对小卫星的分析可作为ALT的一个标志物。已知ALT+细胞中的端粒长度维持依赖于MRN [MRE11（减数分裂重组11）-Rad50-NBS1（尼曼-匹克氏症候群1）]复合物，但包括沃纳（WRN）和布卢姆（BLM）综合征DNA解旋酶基因在内的其他基因的作用仍知之甚少。
