The heterotrimeric eukaryotic Replication protein A (RPA) is a master regulator of numerous DNA metabolic processes. For a long time, it has been viewed as an inert protector of ssDNA and a platform for assembly of various genome maintenance and signaling machines. Later, the modular organization of the RPA DNA binding domains suggested a possibility for dynamic interaction with ssDNA. This modular organization has inspired several models for the RPA-ssDNA interaction that aimed to explain how RPA, the high-affinity ssDNA binding protein, is replaced by the downstream players in DNA replication, recombination, and repair that bind ssDNA with much lower affinity. Recent studies, and in particular single-molecule observations of RPA-ssDNA interactions, led to the development of a new model for the ssDNA handoff from RPA to a specific downstream factor where not only stability and structural rearrangements but also RPA conformational dynamics guide the ssDNA handoff. Here we will review the current knowledge of the RPA structure, its dynamic interaction with ssDNA, and how RPA conformational dynamics may be influenced by posttranslational modification and proteins that interact with RPA, as well as how RPA dynamics may be harnessed in cellular decision making.

异三聚体真核复制蛋白 A (RPA) 是众多 DNA 代谢过程的主要调节因子。长期以来，它一直被视为单链DNA的惰性保护者和组装各种基因组维护和信号机器的平台。后来，RPA DNA 结合域的模块化组织表明了与单链 DNA 动态相互作用的可能性。这种模块化组织激发了 RPA-ssDNA 相互作用的多个模型，旨在解释 RPA（高亲和力 ssDNA 结合蛋白）如何被 DNA 复制、重组和修复中的下游参与者所取代，这些下游参与者以低得多的亲和力结合 ssDNA。最近的研究，特别是 RPA-ssDNA 相互作用的单分子观察，开发了一种新的 ssDNA 从 RPA 切换到特定下游因子的模型，其中不仅稳定性和结构重排，而且 RPA 构象动力学也指导 ssDNA不可触摸。在这里，我们将回顾目前对 RPA 结构、其与 ssDNA 的动态相互作用的了解，以及 RPA 构象动力学如何受到翻译后修饰和与 RPA 相互作用的蛋白质的影响，以及如何在细胞决策中利用 RPA 动力学。