title: Structural and functional analyses of disease-causing missense mutations in Bloom syndrome protein.
abstract: Bloom syndrome (BS) is an autosomal recessive disorder characterized by genomic instability and the early development of many types of cancer. Missense mutations have been identified in the BLM gene (encoding a RecQ helicase) in affected individuals, but the molecular mechanism and the structural basis of the effects of these mutations remain to be elucidated. We analysed five disease-causing missense mutations that are localized in the BLM helicase core region: Q672R, I841T, C878R, G891E and C901Y. The disease-causing mutants had low ATPase and helicase activities but their ATP binding abilities were normal, except for Q672, whose ATP binding activity was lower than that of the intact BLM helicase. Mutants C878R, mapping near motif IV, and G891E and C901Y, mapping in motif IV, displayed severe DNA-binding defects. 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 binding to ATP hydrolysis and DNA unwinding. Our findings will help to explain the mechanism underlying BLM catalysis and interpreting new BLM causing mutations identified in the future.
authors: CNRS, UMR 2027, Institut Curie-Section de Recherche, Centre Universitaire, Bâtiment 110, F-91405 Orsay, France.
authors: Rong-Bing
authors: RB
authors: Guo
authors: Pascal
authors: P
authors: Rigolet
authors: Hua
authors: H
authors: Ren
authors: Bo
authors: B
authors: Zhang
authors: Xing-Dong
authors: XD
authors: Zhang
authors: Shuo-Xing
authors: SX
authors: Dou
authors: Peng-Ye
authors: PY
authors: Wang
authors: Mounira
authors: M
authors: Amor-Gueret
authors: Xu Guang
authors: XG
authors: Xi
mesh_terms: D000251:Adenosine Triphosphatases / Q000737:chemistry* / Q000235:genetics* / Q000378:metabolism; D000595:Amino Acid Sequence; D001816:Bloom Syndrome / Q000235:genetics*; D004247:DNA / Q000378:metabolism; D004265:DNA Helicases / Q000737:chemistry* / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D053484:RecQ Helicases
chemical_list: D004247:DNA; D000251:Adenosine Triphosphatases; C097151:Bloom syndrome protein; D004265:DNA Helicases; D053484:RecQ Helicases