Abstract DNA replication stress is incurred by endogenous or environmental challenges to replication fork progression that impede faithful genome duplication. Genomic G-quadruplexes (G4s) are DNA secondary structures that present a substantial barrier for passage of the replisome, and DNA synthesis past these structures requires dynamic remodeling by specialized helicases, translocases, and other G4-binding proteins to facilitate G4 resolution or bypass. Mutations in the genes encoding these auxiliary replication proteins are linked to hereditary disorders presenting with a range of clinical features, including immunodeficiency, growth restriction, congenital abnormalities, and cancer predisposition, demonstrating that these G4-metabolizing proteins also play broader roles in genome biology such as the replication stress response or DNA repair. Here, we review rare diseases linked to mutations in G4-resolving and binding proteins, with an emphasis on molecular defects in G4 metabolism that incur replication stress and genomic instability. We discuss differences in G4 substrate specificity and mechanism of G4-interactive helicases, as revealed by high-resolution structural data. Furthermore, we address outstanding questions that provide insight into the etiology of rare diseases marked by dysregulated G4 homeostasis and may inform diagnosis and potential therapeutic strategies.
Herr et al. (2026) studied this question.