University of Veterinary Medicine Vienna Novel mutations in the RECQL4 gene affect its helicase functions, interactions with the BLM helicase and chemotherapeutics-induced cell death RecQ family of DNA helicases play pivotal roles in DNA replication, repair and responses to DNA damage or replication stress. Several human RecQ helicases are defective in diseases associated with chromosomal instability, premature aging and cancer. We recently discovered novel mutations in the RECQL4 gene in glioblastoma (GBM), the most malignant brain tumor in adults. Transcriptomic profiles of GBMs with REQCL4 mutations resembled those in REQCL4 KO glioma cells. We employ structural modelling and biochemical approaches to elucidate impacts of novel mutations on RECQL4 helicase activities. Using recombinant RECQL4P532S and RECQL4R766Q proteins we demonstrate that P532S substitution reduces the RECQL4 ability to unwind DNA and disrupts DNA-coupled ATP-hydrolysis activity. WT and mutated RECQL4 were overexpressed in RECQL4 KO glioma cells to study interactions with BLM helicases, cell viability and specific responses to UVC- and chemotherapy-induced DNA damage/repair. Overexpression of RECQL4P532S or RECQL4R766Q variants affected DNA repair and responses to chemotherapeutics in glioma cells, and RECQL4R766Q disturbed interactions with the BLM helicase. Our results reveal deleterious consequences of novel RECQL4 mutations in GBMs. The newly identified RECQL4 mutations affect RECQL4 helicases and their interactions with BLM contributing to glioma progression. en TEXT journal article Wissenschaftlicher Artikel Articolo scientifico Documento PDF Articolo scientifico Text journal article Text Wissenschaftlicher Artikel Cancer Genomics DNA Damage And Repair Molecular Modelling 2025 2025 Agnieszka Kaczmarczyk Mikolaj Sokolowski Kamil Wojnicki Marta Pabis Bartosz Wojtas Iwona A. Ciechomska Katarzyna Poleszak Bartlomiej Gielniewski Sylwia K. Król Matthew Guille Sebastian Glatt Bozena Kaminska Springer