Hrq1, a Homolog of the Human RecQ4 Helicase, Acts Catalytically and Structurally to Promote Genome Integrity

Abstract

Human RecQ4 affects cancer and aging, but it is difficult to study because it is a fusion between a helicase and an essential replication factor. Budding yeast Hrq1 is homologous to the diseaselinked helicase domain of RecQ4 and, like hRecQ4, was a robust 3’–5’ helicase. Additionally, Hrq1 had the unusual property of forming heptameric rings. Cells lacking Hrq1 exhibited two particularly dangerous DNA damage phenotypes: hypersensitivity to DNA inter-strand crosslinks (ICLs) and telomere addition to DNA breaks. Both activities are rare: their co-existing in a single protein is unprecedented. Resistance to ICLs required helicase activity, but suppression of telomere addition did not. Hrq1 also affected telomere length by a non-catalytic mechanism, as well as telomerase-independent telomere maintenance. As Hrq1 bound telomeres in vivo, it likely affects them directly. Thus, the tumor suppressing activity of RecQ4 could be due to a role in ICL repair and/or suppressing de novo telomere addition.