Sequence fingerprints in BRCA2 and RAD51: implications for DNA repair and cancer
Sequence fingerprints in BRCA2 and RAD51: implications for DNA repair and cancer
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DOI：
10.1016/s1568-7864(03)00097-1
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发表时间：
2003-09-18
期刊：
影响因子：
3.8
通讯作者：
Blundell, TL
中科院分区：
文献类型：
--
作者：
Lo, T;Pellegrini, L;Blundell, TL
在人类中，乳腺癌易感蛋白BRCA 2和RAD 51重组酶之间的相互作用对于通过同源重组（HR）进行DNA修复是必不可少的，其失败可能易患癌症。这种相互作用通过BRCA 2中编码的保守BRC重复基序直接与RAD 51结合而发生。在这里，我们描述了完整的和部分BRCA 2同系物从广泛的真核生物，包括果蝇和两个疟原虫物种。人BRC 4-RAD 51复合物的晶体结构允许鉴定对蛋白质-蛋白质相互作用重要的残基，并定义了BRC重复序列和RAD 51的相互作用序列指纹。这些使我们能够预测，大多数真核生物的RAD 51和BRC重复直系同源物应该能够相互作用。我们发现没有证据表明酵母，酵母菌和细菌中存在BRC重复序列，并且它们的RAD 51直系同源物不符合结合BRC重复序列的标准。类似地，预测人RAD 51旁系同源物，包括RAD 51 B、RAD 51 C、RAD 51 D、XRCC 2、XRCC 3和DMC 1不结合BRC重复。BRC重复序列和RAD 51序列指纹在广泛的真核生物物种中的保守性证实了BRCA 2-RAD 51相互作用的功能意义。多个BRC重复序列对RAD 51具有结合特异性的想法使我们提出了BRCA 2参与RAD 51核蛋白丝形成的可能模型。(C)2003 Elsevier B. V.保留所有权利。
In humans, the interactions between the breast cancer susceptibility protein, BRCA2, and the RAD51 recombinase are essential for DNA repair by homologous recombination (HR), failure of which can predispose to cancer. The interactions occur through conserved BRC repeat motifs, encoded in BRCA2, binding directly to RAD51. Here, we describe full and partial BRCA2 homologues from a wide range of eukaryotes, including Drosophila melanogaster and two Plasmodium species. The crystal structure of the human BRC4-RAD51 complex allows identification of residues that are important for protein-protein interaction, and defines interaction sequence fingerprints for the BRC repeat and for RAD51. These allow us to predict that most eukaryotic RAD51 and BRC repeat orthologues should be capable of mutual interactions. We find no evidence for the presence of BRC repeats in yeast, Archaea and bacteria, and their RAD51 orthologues do not fulfil the criteria for binding the BRC repeat. Similarly, human RAD51 paralogues, including RAD51B, RAD51C, RAD51D, XRCC2, XRCC3 and DMC1, are not predicted to bind the BRC repeat. Conservation of the BRC repeat and RAD51 sequence fingerprints across a wide range of eukaryotic species substantiates the functional significance of the BRCA2-RAD51 interactions. The idea of multiple BRC repeats with binding specificity towards RAD51 leads us to suggest a possible model for the participation of BRCA2 in RAD51 nucleoprotein filament formation. (C) 2003 Elsevier B.V. All rights reserved.