Mutations in the RAD54 recombination gene in primary cancers
Mutations in the RAD54 recombination gene in primary cancers
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DOI：
10.1038/sj.onc.1202692
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发表时间：
1999-06-03
期刊：
影响因子：
8
通讯作者：
Kamiya, K
中科院分区：
文献类型：
--
作者：
Matsuda, M;Miyagawa, K;Kamiya, K
重组修复蛋白RAD 51与肿瘤抑制因子BRCA 1和BRCA 2的关联表明同源重组中的缺陷是肿瘤形成的原因。此外，最近的研究结果表明，与MRE 11/RAD 50修复复合物相关的蛋白质在奈梅亨断裂综合征中发生突变，其特征是癌症发病率和电离辐射敏感性增加，这强烈支持了这一观点。然而，BRCA蛋白和负责NBS的蛋白在重组修复中的直接作用尚不清楚，尽管它们与重组修复复合物有关。由于RAD 51与RAD 52上位组的其他成员和BRCA蛋白形成复合物，因此询问RAD 52上位组成员的改变是否导致肿瘤发展是合理的。在这里，我们描述了错义突变的功能区域的RAD 54和野生型RAD 54表达的情况下，在原发性癌症的异常剪接。由于RAD 54是一种与RAD 51相关的重组蛋白，这是第一个遗传证据表明癌症是由同源重组修复过程中的缺陷引起的。
Association of a recombinational repair protein RAD51 with tumor suppressors BRCA1 and BRCA2 suggests that defects in homologous recombination are responsible for tumor formation. Also recent findings that a protein associated with the MRE11/RAD50 repair complex is mutated in Nijmegen breakage syndrome characterized by increased cancer incidence and ionizing radiation sensitivity strongly support this idea. However, the direct roles of BRCA proteins and the protein responsible for NBS in recombinational repair are not clear though they are associated with the recombinational repair complexes. Since RAD51 forms a complex with other members of the RAD52 epistasis group and with BRCA proteins, it is reasonable to ask if alterations of members of the RAD52 epistasis group lead to tumor development. Here we describe missense mutations at functional regions of RAD54 and the absence of the wild-type RAD54 expression resulting from aberrant splicing in primary cancers. Since RAD54 is a recombinational protein associated with RAD51, this is the first genetic evidence that cancer arises from a defect in repair processes involving homologous recombination.