Department of Genetics, The Silberman Institute of Life Sciences, The Hebrew University of Jerusalem, Givat Ram, Jerusalem 91904, Israel.
INSERM UMR 1163, Laboratory of Genome Dynamics in the Immune System, Equipe Labellisée Ligue contre le Cancer and Paris Descartes-Sorbonne Paris Cité University, Imagine Institute, Paris, France.
Nucleic Acids Res. 2020 Jul 27;48(13):7239-7251. doi: 10.1093/nar/gkaa503.
Telomeres cap the ends of eukaryotic chromosomes and distinguish them from broken DNA ends to suppress DNA damage response, cell cycle arrest and genomic instability. Telomeres are elongated by telomerase to compensate for incomplete replication and nuclease degradation and to extend the proliferation potential of germ and stem cells and most cancers. However, telomeres in somatic cells gradually shorten with age, ultimately leading to cellular senescence. Hoyeraal-Hreidarsson syndrome (HHS) is characterized by accelerated telomere shortening and diverse symptoms including bone marrow failure, immunodeficiency, and neurodevelopmental defects. HHS is caused by germline mutations in telomerase subunits, factors essential for its biogenesis and recruitment to telomeres, and in the helicase RTEL1. While diverse phenotypes were associated with RTEL1 deficiency, the telomeric role of RTEL1 affected in HHS is yet unknown. Inducible ectopic expression of wild-type RTEL1 in patient fibroblasts rescued the cells, enabled telomerase-dependent telomere elongation and suppressed the abnormal cellular phenotypes, while silencing its expression resulted in gradual telomere shortening. Our observations reveal an essential role of the RTEL1 C-terminus in facilitating telomerase action at the telomeric 3' overhang. Thus, the common etiology for HHS is the compromised telomerase action, resulting in telomere shortening and reduced lifespan of telomerase positive cells.
端粒覆盖真核染色体的末端，并将其与断裂的 DNA 末端区分开来，以抑制 DNA 损伤反应、细胞周期停滞和基因组不稳定性。端粒通过端粒酶延长，以补偿不完全复制和核酶降解，并延长生殖细胞和干细胞以及大多数癌症的增殖潜力。然而，体细胞中的端粒随着年龄的增长逐渐缩短，最终导致细胞衰老。Hoyeraal-Hreidarsson 综合征（HHS）的特征是端粒缩短加速，多种症状包括骨髓衰竭、免疫缺陷和神经发育缺陷。HHS 是由端粒酶亚基、其生物发生所必需的因素以及解旋酶 RTEL1 的种系突变引起的。虽然与 RTEL1 缺陷相关的表型多种多样，但在 HHS 中受影响的 RTEL1 的端粒作用尚不清楚。在患者成纤维细胞中诱导异位表达野生型 RTEL1 可挽救细胞，使端粒酶依赖性端粒延长，并抑制异常的细胞表型，而沉默其表达则导致端粒逐渐缩短。我们的观察结果揭示了 RTEL1 C 末端在促进端粒酶在端粒 3'突出端发挥作用中的重要作用。因此，HHS 的共同病因是端粒酶作用受损，导致端粒缩短和端粒酶阳性细胞寿命缩短。
