摘要
40 %～ 5 0 %的遗传性乳腺癌和至少 80 %的既有乳腺癌又有卵巢癌家族史的患者是由BRCA1突变引起的 .BRCA1C末端含有 2个BRCT结构域 (BRCT1和BRCT2 ) ,它们与BRCA1的重要功能密切相关 .许多乳腺癌易感突变发生在BRCA1的BRCT结构域中 .利用染色质结构检测技术表明 ,BRCT结构域具有染色质伸展活性 .利用缺失突变技术构建了 6种BRCT2结构域 (175 6～ 185 2位氨基酸残基 )缺失突变体并将BRCT2结构域中与染色质伸展相关的重要区域定位到 175 6～ 180 8之间的氨基酸残基 ;用丙氨酸扫描技术构建了 6种BRCT2结构域丙氨酸扫描突变体并将重要氨基酸残基序列定位到 1784～ 1788之间的VQLCG .BRCT2结构域的定位有助于预测BRCT2结构域突变后发生乳腺癌的风险 ,也为进一步研究BRCT2结构域的功能机制提供了有用的材料 .
Breast cancer susceptibility gene 1( BRCA1) is mutated in approximately 40%～50% of familial breast cancers and more than 80% of inherited breast and ovarian cancers. There are two repeats of BRCA1 C terminal domain at its C temimus(BRCT1 and BRCT2) that is required for its function in both transcriptional activation and DNA repair. Many cancer predisposing mutations are located in the BRCT domains, which have been shown to induce chromatin unfolding by use of an approach that allows visualization of large scale chromatin structure through lac repressor/lac operator recognition. To map the important region of BRCT2 domain (amino acid residues 1756—1852), six deletion mutant constructs were made. The chromatin structure assay showed that amino acid residues 1756—1808 are involved in the induction of chromatin unfolding. To further localize the critical amino acid residues, six alanine scanning mutant constructs were made. The chromatin structure assay demonstrated that the 1784VQLCG1788 region is critical for the chromatin unfolding activity. Mapping of the BRCT2 domain may aid in the presymptomatic risk assessment and provide a valuable tool for further study on the BRCT1 structure and function.
出处
《中国生物化学与分子生物学报》
CAS
CSCD
北大核心
2003年第4期469-474,共6页
Chinese Journal of Biochemistry and Molecular Biology
