RTEL1: functions of a disease-associated helicase

•RTEL1 is an Fe–S helicase that controls homologous recombination by dismantling D-loop intermediates.•RTEL1 maintains telomere integrity by disassembling T-loops and counteracting G4-DNA structures.•RTEL1 variants strongly associate with predisposition to glioma, astrocytoma, and glioblastoma.•Mutations in RTEL1 give rise to Hoyeraal–Hreidarsson syndrome.

DNA secondary structures that arise during DNA replication, repair, and recombination (3R) must be processed correctly to prevent genetic instability. Regulator of telomere length 1 (RTEL1) is an essential DNA helicase that disassembles a variety of DNA secondary structures to facilitate 3R processes and to maintain telomere integrity. The past few years have witnessed the emergence of RTEL1 variants that confer increased susceptibility to high-grade glioma, astrocytomas, and glioblastomas. Mutations in RTEL1 have also been implicated in Hoyeraal–Hreidarsson syndrome, a severe form of the bone-marrow failure and cancer predisposition disorder, dyskeratosis congenita. We review these recent findings and highlight its crucial link between DNA secondary-structure metabolism and human disease.