Tan Rong, Lan Li
Xiangya Hospital, Central South University, Changsha 410008, China University of Pittsburgh Cancer Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, PA 15219, USA.
University of Pittsburgh Cancer Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, PA 15219, USA
Acta Biochim Biophys Sin (Shanghai). 2016 Jul;48(7):617-22. doi: 10.1093/abbs/gmw040. Epub 2016 May 12.
The ends of each chromosome are capped by the telomere assembly to protect chromosomal integrity from telomere attrition and DNA damage. In response to DNA damage, DNA repair factors are enriched at damage sites by a sophisticated signaling and recruitment cascade. However, DNA damage response at telomeres is different from non-telomeric region of genomic DNA due to specialized sequences and structures of the telomeres. In the course of normal DNA replication or DNA damage repair, both the telomere shelterin protein complex and the condensed telomeric chromatin structure in mammalian cells are modified to protect telomeres from exposing free DNA ends which are subject to both telemere shortening and chromosome end fusion. Initiation of either homologous recombination or non-homologous end joint repair at telomeres requires disassembling and/or post-translational modifications of the shelterin complex and telomeric chromatin. In addition, cancer cells utilize distinct mechanisms to maintain telomere length and cell survival upon damage. In this review, we summarize current studies that focus on telomere end protection and telomere DNA repair using different methodologies to model telomere DNA damage and disruption. These include genetic ablation of sheltering proteins, targeting endonuclease to telomeres, and delivering oxidative damage directly. These different approaches, when combined, offer better understanding of the mechanistic differences in DNA damage response between telomeric and genomic DNA, which will provide new hope to identify potential cancer therapeutic targets to curtail cancer cell proliferation via induction of telomere dysfunctions.
每个染色体的末端由端粒组件覆盖，以保护染色体完整性免受端粒磨损和DNA损伤。响应DNA损伤时，DNA修复因子通过复杂的信号传导和招募级联在损伤位点富集。然而，由于端粒的特殊序列和结构，端粒处的DNA损伤反应不同于基因组DNA的非端粒区域。在正常DNA复制或DNA损伤修复过程中，哺乳动物细胞中的端粒保护蛋白复合物和浓缩的端粒染色质结构都会被修饰，以保护端粒不暴露游离的DNA末端，这些末端会导致端粒缩短和染色体末端融合。端粒处同源重组或非同源末端连接修复的启动需要拆卸和/或对保护蛋白复合物和端粒染色质进行翻译后修饰。此外，癌细胞利用不同的机制在损伤后维持端粒长度和细胞存活。在这篇综述中，我们总结了当前的研究，这些研究使用不同的方法模拟端粒DNA损伤和破坏，重点关注端粒末端保护和端粒DNA修复。这些方法包括对保护蛋白进行基因敲除、将核酸内切酶靶向端粒以及直接造成氧化损伤。这些不同的方法结合起来，可以更好地理解端粒DNA和基因组DNA在DNA损伤反应中的机制差异，这将为通过诱导端粒功能障碍来识别潜在的癌症治疗靶点以抑制癌细胞增殖提供新的希望。
