Telomere Length Regulation Unit, Children's Medical Research Institute, University of Sydney, Westmead, NSW 2145, Australia.
Telomere Length Regulation Unit, Children's Medical Research Institute, University of Sydney, Westmead, NSW 2145, Australia.
Trends Genet. 2017 Dec;33(12):921-932. doi: 10.1016/j.tig.2017.09.003. Epub 2017 Sep 29.
Telomeres shorten during each cellular division, with cumulative attrition resulting in telomeric damage and replicative senescence. Bypass of replicative senescence precipitates catastrophic telomere shortening or crisis, and is characterized by widespread genomic instability. Activation of a telomere maintenance mechanism (TMM) is necessary to stabilise the genome and establish cellular immortality through the reconstitution of telomere capping function. The alternative lengthening of telomeres (ALT) pathway is a TMM frequently activated in tumors of mesenchymal or neuroepithelial origin. ALT is a homology-directed recombination-dependent replication pathway that utilizes telomeric templates for synthesis; however, its precise protein requirements have remained elusive. Recently, several developments have shed light on the DNA repair pathways that become engaged at ALT telomeres, implicating ALT telomeres as DNA repair hot spots. Here, we review recent discoveries regarding the ALT mechanism, and discuss how DNA repair pathways converge to maintain the length and functional integrity of telomeres in ALT cancers.
端粒在每次细胞分裂中都会缩短，随着累积的损耗，导致端粒损伤和复制性衰老。复制性衰老的旁路会导致灾难性的端粒缩短或危机，并伴有广泛的基因组不稳定性。激活端粒维持机制 (TMM) 对于稳定基因组和通过重建端粒盖帽功能来建立细胞永生是必要的。端粒的替代性延长 (ALT) 途径是一种 TMM，常被激活于间充质或神经上皮来源的肿瘤中。ALT 是一种依赖同源重组的复制途径，利用端粒模板进行合成；然而，其确切的蛋白质需求仍然难以捉摸。最近，一些新的发现揭示了参与 ALT 端粒的 DNA 修复途径，表明 ALT 端粒是 DNA 修复热点。在这里，我们回顾了关于 ALT 机制的最新发现，并讨论了 DNA 修复途径如何汇聚以维持 ALT 癌症中端粒的长度和功能完整性。
