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.

中文翻译：

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人类RTEL1稳定长G突出端，从而允许端粒酶依赖性过度延伸

端粒维持可以保护细胞免受基因组不稳定和衰老的影响。端粒加速磨损是包括先天性角化病（DC）在内的早衰综合症的特征。hRTEL1中的突变与一种称为Hoyeraal-Hreidarsson综合征（HHS）的DC的严重形式有关。HHS患者携带短端粒，HHS细胞显示端粒受损。在这里，我们研究了hRTEL1如何促进人类原发性以及肿瘤细胞中端粒的维持。hRTEL1的瞬时耗竭仅在端粒酶阳性细胞具有非常长的端粒和高水平的端粒酶的情况下才导致端粒快速缩短。hRTEL1对端粒长度的影响是端粒酶依赖性的，而不会影响端粒酶的生物发生或将酶靶向端粒。反而，RTEL1耗尽导致端粒解开受限的端粒的G突出端含量和POT1缔合减少。令人惊讶的是，POT1的过表达恢复了端粒的长度，但未恢复突出端，表明G突出端丢失是由RTEL1耗尽引起的主要缺陷。我们提出，hRTEL1通过保留长G突出端而有助于长端粒的维持，从而促进POT1结合和端粒酶的延长。