Nucleic Acids Research Advance Access published online on September 18, 2007
Nucleic Acids Research, doi:10.1093/nar/gkm536
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Nucleic Acid Enzymes |
Structural and functional analyses of disease-causing missense mutations in Bloom syndrome protein
1CNRS, UMR 2027, Institut Curie – Section de Recherche, Centre Universitaire, Bâtiment 110, F-91405 Orsay, 2CNRS UMR 8113, Ecole Normale Supérieure (ENS) Cachan, 61 avenue du Président Wilson, 94235 Cachan cedex, France, 3School of Life Science, East China Normal University, Science Building, 3663 North Zhongshan Road, Shanghai 200062 and 4Laboratory of Soft Matter Physics, Beijing National Laboratory for Condensed Matter Physics, Institute of Physics, Chinese Academy of Sciences, Beijing 100080, China
*To whom correspondence should be addressed. Tel: +33 1 69 86 31 81; Fax: +33 1 69 86 94 29; Email: xu-guang.xi{at}curie.u-psud.fr
Received March 5, 2007. Revised June 11, 2007. Accepted June 27, 2007.
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.
The authors wish it to be known that, in their opinion, the first two authors should be regarded as joint First Authors.