Guo Rong-Bing, Rigolet Pascal, Ren Hua, Zhang Bo, Zhang Xing-Dong, Dou Shuo-Xing, Wang Peng-Ye, Amor-Gueret Mounira, Xi Xu Guang
CNRS, UMR 2027, Institut Curie-Section de Recherche, Centre Universitaire, Bâtiment 110, F-91405 Orsay, France.
Nucleic Acids Res. 2007;35(18):6297-310. doi: 10.1093/nar/gkm536. Epub 2007 Sep 18.
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.
布卢姆综合征（BS）是一种常染色体隐性疾病，其特征为基因组不稳定以及多种癌症的早期发生。在受影响个体的BLM基因（编码一种RecQ解旋酶）中已鉴定出错义突变，但这些突变影响的分子机制和结构基础仍有待阐明。我们分析了位于BLM解旋酶核心区域的五个致病错义突变：Q672R、I841T、C878R、G891E和C901Y。致病突变体的ATP酶和解旋酶活性较低，但除Q672外，其ATP结合能力正常，Q672的ATP结合活性低于完整的BLM解旋酶。位于基序IV附近的突变体C878R以及位于基序IV中的G891E和C901Y表现出严重的DNA结合缺陷。我们使用分子建模来分析这些突变。我们的工作为BLM病理学的分子基础提供了见解，并揭示了与将DNA结合与ATP水解及DNA解旋偶联相关的结构元件。我们的发现将有助于解释BLM催化的机制，并有助于解读未来鉴定出的新的BLM致病突变。
