Discovery of a new hereditary RECQ helicase disorder RECON syndrome positions the replication stress response and genome homeostasis as centrally important processes in aging and age-related disease.

Abstract

Characterizing the molecular deficiencies underlying human aging has been a formidable challenge as it is clear that a complex myriad of factors including genetic mutations, environmental influences, and lifestyle choices influence the deterioration responsible for human pathologies. In addition, the common denominators of human aging, exemplified by the newly updated hallmarks of aging (López-Otín et al., 2023), suggest multiple avenues and layers of crosstalk between pathways important for genome and cellular homeostasis, both of which are major determinants of both good health and lifespan. In this regard, we postulate that hereditary disorders characterized by chromosomal instability offer a unique window of insight into aging and age-related disease processes. Recently, we discovered a new RECQ helicase disorder, designated RECON syndrome attributed to bi-allelic mutations in the RECQL1 gene (Abu-Libdeh et al., 2022). Cells deficient in RECQL1 exhibit genomic instability and a compromised response to replication stress, providing further evidence for the significance of genome homeostasis to suppress disease phenotypes. Here we provide a perspective on the pathology of RECON syndrome to inform the reader as to how molecular defects in the RECQL1 gene contribute to underlying deficiencies in nucleic acid metabolism often seen in certain aging or age-related diseases.