Structural and functional analyses of disease-causing missense mutations in Bloom syndrome protein
Journal - Nucleic Acids Research
Bloom syndrome (BS) is an autosomal recessive disorder characterizedby genomic instability and the early development of many typesof cancer. Missense mutations have been identified in the BLMgene (encoding a RecQ helicase) in affected individuals, butthe molecular mechanism and the structural basis of the effectsof these mutations remain to be elucidated. We analysed fivedisease-causing missense mutations that are localized in theBLM helicase core region: Q672R, I841T, C878R, G891E and C901Y.The disease-causing mutants had low ATPase and helicase activitiesbut their ATP binding abilities were normal, except for Q672,whose ATP binding activity was lower than that of the intactBLM helicase. Mutants C878R, mapping near motif IV, and G891Eand C901Y, mapping in motif IV, displayed severe DNA-bindingdefects. We used molecular modelling to analyse these mutations.Our work provides insights into the molecular basis of BLM pathology,and reveals structural elements implicated in coupling DNA bindingto ATP hydrolysis and DNA unwinding. Our findings will helpto explain the mechanism underlying BLM catalysis and interpretingnew BLM causing mutations identified in the future.