Inherited mutations in the helicase RTEL1 cause telomere dysfunction and Hoyeraal–Hreidarsson syndrome

Abstract

Telomeres repress the DNA damage response at the natural chromosome ends to prevent cell-cycle arrest and maintain genome stability. Telomeres are elongated by telomerase in a tightly regulated manner to ensure a sufficient number of cell divisions throughout life, yet prevent unlimited cell division and cancer development. Hoyeraal-Hreidarsson syndrome (HHS) is characterized by accelerated telomere shortening and a broad range of pathologies, including bone marrow failure, immunodeficiency, and developmental defects. HHS-causing mutations have previously been found in telomerase and the shelterin component telomeric repeat binding factor 1 (TRF1)-interacting nuclear factor 2 (TIN2). We identified by whole-genome exome sequencing compound heterozygous mutations in four siblings affected with HHS, in the gene encoding the regulator of telomere elongation helicase 1 (RTEL1). Rtel1 was identified in mouse by its genetic association with telomere length. However, its mechanism of action and whether it regulates telomere length in human remained unknown. Lymphoblastoid cell lines obtained from a patient and from the healthy parents carrying heterozygous RTEL1 mutations displayed telomere shortening, fragility and fusion, and growth defects in culture. Ectopic expression of WT RTEL1 suppressed the telomere shortening and growth defect, confirming the causal role of the RTEL1 mutations in HHS and demonstrating the essential function of human RTEL1 in telomere protection and elongation. Finally, we show that human RTEL1 interacts with the shelterin protein TRF1, providing a potential recruitment mechanism of RTEL1 to telomeres. dyskeratosis congenita | genomic instability | aging | telomeropathies H uman telomeres are composed of tandem TTAGGG DNA repeats, ending with an essential single-stranded 3′-overhang (reviewed in refs. 1 and 2). This overhang can be elongated by the enzyme telomerase to make up for losses caused by incomplete DNA replication and degradation. The expression of the telomerase reverse-transcriptase subunit (hTERT) is suppressed in most human somatic tissues; consequently, telomeres gradually shorten with each cell division. Critically short telomeres activate the DNA damage response (DDR) and cause cell-cycle arrest or apoptosis. Thus, telomere length and integrity control cellular lifespan and provide a tumor-suppressing mechanism (3). Shelterin, a complex of six core proteins, assembles at mammalian telomeres to suppress DDR and regulate telomere length (4, 5). Shelterin was suggested to facilitate the formation of a telomere (T)-loop, via invasion of double-stranded telomeric DNA by the 3′ overhang, where it is inaccessible to DDR factors and to telomerase.Dyskeratosis congenita (DC) and its severe form HoyeraalHreidarsson syndrome (HHS) are hereditary disorders associated with severely shortened telomeres and diverse clinical symptoms (6-8). The major cause of death in DC and HHS is bone marrow failure, but mortality from cancer and pulmonary fibrosis also occurs at frequencies above normal. Mu...

Myelodysplasia and liver disease extend the spectrum of RTEL1 related telomeropathies

“…However, we now note that these individuals may nevertheless be predisposed to developing disease in their later years. This is suggested by Family 2 ( Figure 1A, p.G1096W) where there is a history of pulmonary disease in the grandmother in her 70s and for the p.R998* variant, which has been seen in both severe recessive 3,5,6 and late onset dominant settings (Families 4 and 8 and Cogan et al 7 ). Thus, it is important to be careful when counselling families.…”

Extended clinical and genetic spectrum associated with biallelic RTEL1 mutations

“…1,[4][5][6] Other researchers and we recently reported patients with HH carrying mutations in RTEL1, a gene encoding a DNA helicase. [7][8][9][10][11][12] RTEL1 belongs to a family of iron-sulfur-clustercontaining DNA helicases; other members include XPD, FANCJ, and DDX11/ChlR1. 13 The helicase domain of RTEL1 exerts an in vitro antirecombinogenic activity by displacing DNA recombination intermediates, the so-called D-loop.…”

RTEL1, une hélicase de l’ADN essentielle à la stabilité du génome

“…Cette proposition semble être confortée par l'observation d'une augmentation des cercles T au cours de la réplication des cellules déficientes en Rtel1 [12] (Figure 2). Dans ce contexte, l'excision de la boucle T semble principalement impliquer le complexe nucléase SLX4 [12,26] (Figure 3) [6,8,9,13,15]. Au total, ces différentes explorations permettent de décrire à ce jour 14 patients atteints de DC/HH porteurs de mutation dans le gène RTEL1.…”

“…Par ailleurs, la même étude relate une légère augmentation du nombre de cercles T dans les cellules de ces patients. Cependant, deux autres études indépendantes n'ont pu confirmer la présence (ou l'augmentation) de cercles T dans différents types de cellules de plusieurs patients défi-cients en RTEL1 (T. Le Guen et P. Revy, données non publiées, et [8] …”

“…Certains de ces facteurs, spécifiquement localisés aux télomères, participent à leur homéosta-sie et leur protection ; d'autres sont nécessaires à la stabilité globale du génome. Plusieurs travaux récents ont permis d'identifier RTEL1 comme un acteur crucial tant pour le maintien des télomères que pour la stabilité du génome dans son ensemble [6][7][8][9][10][11][12][13][14][15][16][17].…”