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Article Dans Une Revue Nucleic Acids Research Année : 2020

Full length RTEL1 is required for the elongation of the single-stranded telomeric overhang by telomerase

Aya Awad
Galina Glousker
  • Fonction : Auteur
Noa Lamm
  • Fonction : Auteur
Shadi Tawil
  • Fonction : Auteur
Noa Hourvitz
  • Fonction : Auteur
Riham Smoom
  • Fonction : Auteur
Yehuda Tzfati
  • Fonction : Auteur

Résumé

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 biogen-esis and recruitment to telomeres, and in the heli-case 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 etiol-ogy for HHS is the compromised telomerase action, resulting in telomere shortening and reduced lifespan of telomerase positive cells.
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Dates et versions

hal-02997232 , version 1 (10-11-2020)

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Citer

Aya Awad, Galina Glousker, Noa Lamm, Shadi Tawil, Noa Hourvitz, et al.. Full length RTEL1 is required for the elongation of the single-stranded telomeric overhang by telomerase. Nucleic Acids Research, 2020, 48 (13), pp.13 - 7239. ⟨10.1093/nar/gkaa503⟩. ⟨hal-02997232⟩

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