Structure and Instability of Genomes laboratory, "Muséum National d'Histoire Naturelle" (MNHN), Inserm U1154, CNRS UMR 7196, Paris, France.
Hum Mol Genet. 2021 Apr 26;30(3-4):172-181. doi: 10.1093/hmg/ddab008.
Telomere fusions lead to a state of genomic instability, and are thought to drive clonal evolution and tumorigenesis. Telomere fusions occur via both Classical and Alternative Non-Homologous End Joining repair pathways. AsiDNA is a DNA repair inhibitor that acts by mimicking a DNA double strand break (DSB) and hijacking the recruitment of proteins involved in various DNA repair pathways. In this study, we investigated whether the inhibition of DSB-repair pathways by AsiDNA could prevent telomere fusions during crisis. The present study showed that AsiDNA decreased the frequency of telomere fusions without affecting the rate of telomere erosion. Further, it indicated that AsiDNA does not impact the choice of the repair pathway used for the fusion of short dysfunctional telomeres. AsiDNA is thought to prevent short telomeres from fusing by inhibiting DNA repair. An alternative, non-mutually exclusive possibility is that cells harbouring fusions preferentially die in the presence of AsiDNA, thus resulting in a reduction in fusion frequency. This important work could open the way for investigating the use of AsiDNA in the treatment of tumours that have short dysfunctional telomeres and/or are experiencing genomic instability.
端粒融合导致基因组不稳定，并被认为驱动克隆进化和肿瘤发生。端粒融合通过经典和替代非同源末端连接修复途径发生。AsiDNA 是一种 DNA 修复抑制剂，通过模拟 DNA 双链断裂 (DSB) 并劫持参与各种 DNA 修复途径的蛋白质的招募来发挥作用。在这项研究中，我们研究了 AsiDNA 通过抑制 DSB 修复途径是否可以防止危机期间的端粒融合。本研究表明，AsiDNA 降低了端粒融合的频率，而不影响端粒侵蚀的速度。此外，它表明 AsiDNA 并不影响用于融合短功能失调端粒的修复途径的选择。AsiDNA 被认为通过抑制 DNA 修复来防止短端粒融合。另一种非互斥的可能性是，在 AsiDNA 存在的情况下，融合的细胞更倾向于死亡，从而导致融合频率降低。这项重要的工作为研究 AsiDNA 在治疗具有短功能失调端粒和/或经历基因组不稳定的肿瘤中的应用开辟了道路。
