In normal cells, loss of telomeres with each cell division is a normal process limiting the lifespan of cells. However, accelerated telomere shortening, as occurs in the genetic disorder Dyskeratosis Congenita (DC), is associated with reduced cellular lifespan and early onset of several aging-associated pathologies. Bone marrow failure is the primary cause of death in these patients. Hoyeraal Hreidarsson syndrome (HHS) is a clinically severe variant of DC in which patients also display neurodevelopmental defects.

We identified HHS-causing mutation in the helicase Regulator of Telomere Elongation 1 (RTEL1) - an essential helicase that belongs to a small family of iron-sulfur–containing DNA helicases. It was previously identified as a dominant factor that is important for telomere integrity and length regulation in mice. However, how RTEL1 regulates telomere length and how its dysfunction causes HHS remain unknown.

We established an inducible RTEL1 expression system in cells derived from HHS patients carrying various point mutations in RTEL1. The expression of wild-type RTEL1 elongated the telomere and rescued the cells from senescence, and confirmed the causative role of the RTEL1 mutations in the disease.  Our results suggest that RTEL1 is involved in the processing of the telomere end to generate a 3’ overhang that can be elongated by telomerase. We are currently exploiting the naturally occurring RTEL1 mutations and the cell lines established from the patients, as invaluable tools to dissect the function of RTEL1 at telomeres and how do mutations in this gene cause a fatal disease.