Promotion of BRCA2-Dependent Homologous Recombination by DSS1 via RPA Targeting and DNA Mimicry.
Promotion of BRCA2-Dependent Homologous Recombination by DSS1 via RPA Targeting and DNA Mimicry.
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DOI：
10.1016/j.molcel.2015.05.032
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发表时间：
2015-07-16
期刊：
影响因子：
16
通讯作者：
Sung P
中科院分区：
文献类型：
--
作者：
Zhao W;Vaithiyalingam S;San Filippo J;Maranon DG;Jimenez-Sainz J;Fontenay GV;Kwon Y;Leung SG;Lu L;Jensen RB;Chazin WJ;Wiese C;Sung P
肿瘤抑制因子BRCA 2被认为在DNA断裂和复制叉修复期间通过同源重组促进ssDNA从复制蛋白A（RPA）到RAD 51重组酶的传递。但是，我们发现RPA-RAD 51交换需要BRCA 2合作伙伴DSS 1。生物化学、结构和体内分析表明，DSS 1允许BRCA 2-DSS 1复合物与RPA在物理和功能上相互作用。从机制上讲，DSS 1充当DNA模拟物，以减弱RPA对ssDNA的亲和力。DSS 1的暴露于溶剂的酸性结构域中的突变损害了RPA-RAD 51交换的功效。因此，通过靶向RPA和模拟DNA，DSS 1与BRCA 2在基因组维持和肿瘤抑制中的双组分同源重组介体复合物中起作用。我们的发现可能为理解DSS 1在其他生物过程中的作用提供了一个范例。
The tumor suppressor BRCA2 is thought to facilitate the handoff of ssDNA from replication protein A (RPA) to the RAD51 recombinase during DNA break and replication fork repair by homologous recombination. However, we find that RPA-RAD51 exchange requires the BRCA2 partner DSS1. Biochemical, structural, and in vivo analyses reveal that DSS1 allows the BRCA2-DSS1 complex to physically and functionally interact with RPA. Mechanistically, DSS1 acts as a DNA mimic to attenuate the affinity of RPA for ssDNA. A mutation in the solvent-exposed acidic domain of DSS1 compromises the efficacy of RPA-RAD51 exchange. Thus, by targeting RPA and mimicking DNA, DSS1 functions with BRCA2 in a two-component homologous recombination mediator complex in genome maintenance and tumor suppression. Our findings may provide a paradigm for understanding the roles of DSS1 in other biological processes.