Institut Curie, PSL Research University, Sorbonne Universités, CNRS UMR3244 Telomere and cancer lab, 75005 Paris, France.
Department of Genetics, The Silberman Institute of Life Science, The Hebrew University of Jerusalem, Safra Campus-Givat Ram, Jerusalem 91904, Israel.
Nucleic Acids Res. 2018 May 18;46(9):4533-4545. doi: 10.1093/nar/gky173.
Telomere maintenance protects the cell against genome instability and senescence. Accelerated telomere attrition is a characteristic of premature aging syndromes including Dyskeratosis congenita (DC). Mutations in hRTEL1 are associated with a severe form of DC called Hoyeraal-Hreidarsson syndrome (HHS). HHS patients carry short telomeres and HHS cells display telomere damage. Here we investigated how hRTEL1 contributes to telomere maintenance in human primary as well as tumor cells. Transient depletion of hRTEL1 resulted in rapid telomere shortening only in the context of telomerase-positive cells with very long telomeres and high levels of telomerase. The effect of hRTEL1 on telomere length is telomerase dependent without impacting telomerase biogenesis or targeting of the enzyme to telomeres. Instead, RTEL1 depletion led to a decrease in both G-overhang content and POT1 association with telomeres with limited telomere uncapping. Strikingly, overexpression of POT1 restored telomere length but not the overhang, demonstrating that G-overhang loss is the primary defect caused by RTEL1 depletion. We propose that hRTEL1 contributes to the maintenance of long telomeres by preserving long G-overhangs, thereby facilitating POT1 binding and elongation by telomerase.
端粒维持可保护细胞免受基因组不稳定和衰老的影响。端粒加速损耗是包括先天性角化不良症（DC）在内的多种早衰综合征的特征。hRTEL1 突变与一种称为 Hoyeraal-Hreidarsson 综合征（HHS）的严重形式的 DC 相关。HHS 患者携带短端粒，并且 HHS 细胞显示端粒损伤。在这里，我们研究了 hRTEL1 如何在人原代细胞和肿瘤细胞中维持端粒。瞬时耗尽 hRTEL1 仅在端粒酶阳性细胞中导致快速的端粒缩短，这些细胞具有非常长的端粒和高水平的端粒酶。hRTEL1 对端粒长度的影响依赖于端粒酶，而不影响端粒酶的生物发生或酶向端粒的靶向。相反，RTEL1 耗竭导致 G 突出端含量和 POT1 与端粒的结合减少，端粒无盖化有限。引人注目的是，POT1 的过表达恢复了端粒长度，但不能恢复突出端，表明 G 突出端的丢失是 RTEL1 耗竭引起的主要缺陷。我们提出 hRTEL1 通过保留长的 G 突出端来促进端粒酶结合和伸长，从而有助于长端粒的维持。
