Investigating the Effect of Mono- and Dimeric 360A G-Quadruplex Ligands on Telomere Stability by Single Telomere Length Analysis (STELA)
Investigating the Effect of Mono- and Dimeric 360A G-Quadruplex Ligands on Telomere Stability by Single Telomere Length Analysis (STELA)
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DOI：
10.3390/molecules24030577
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发表时间：
2019-02-01
期刊：
影响因子：
4.6
通讯作者：
Roger, Laureline
中科院分区：
文献类型：
--
作者：
Hwang, In Pyo;Mailliet, Patrick;Roger, Laureline
端粒是一种核蛋白结构，它覆盖并保护染色体的自然末端。端粒DNA富含G的链可以形成G-四链体（或G4）结构。结合并稳定G4结构的配体可以通过置换shelterin蛋白和/或通过干扰端粒的复制而导致端粒功能障碍。我们先前报道了两种吡啶二甲酰胺G4配体，360 A及其二聚体类似物（360 A）（2A），能够通过稳定G4结构从端粒DNA中置换hRPA（复制机制的单链DNA结合蛋白）。在本文中，我们进行了第一次单端粒长度分析（STELA）调查的端粒长度和稳定性的G4配体的影响。我们使用STELA的独特能力来揭示用360 A和（360 A）处理的癌细胞中染色体末端的端粒长度的全谱（2A）。在用这些配体处理后，我们很容易检测到超短端粒的增加，其长度显著短于平均端粒长度，并且不能通过其他方法检测到。
Telomeres are nucleoprotein structures that cap and protect the natural ends of chromosomes. Telomeric DNA G-rich strands can form G-quadruplex (or G4) structures. Ligands that bind to and stabilize G4 structures can lead to telomere dysfunctions by displacing shelterin proteins and/or by interfering with the replication of telomeres. We previously reported that two pyridine dicarboxamide G4 ligands, 360A and its dimeric analogue (360A)(2A), were able to displace in vitro hRPA (a single-stranded DNA-binding protein of the replication machinery) from telomeric DNA by stabilizing the G4 structures. In this paper, we perform for the first time single telomere length analysis (STELA) to investigate the effect of G4 ligands on telomere length and stability. We used the unique ability of STELA to reveal the full spectrum of telomere lengths at a chromosome terminus in cancer cells treated with 360A and (360A)(2A). Upon treatment with these ligands, we readily detected an increase of ultrashort telomeres, whose lengths are significantly shorter than the mean telomere length, and that could not have been detected by other methods.