Genomic integrity is most threatened by double-strand breaks, which, if left unrepaired, lead to carcinogenesis or cell death. The cell generates a network of protein–protein signaling interactions that emanate from the DNA damage which are now recognized as a rich basis for anti-cancer therapy development. Deciphering the structures of signaling proteins has been an uphill task owing to their large size and complex domain organization. Recent advances in mammalian protein expression/purification and cryo-EM-based structure determination have led to significant progress in our understanding of these large multidomain proteins. This review is an overview of the structural principles that underlie some of the key signaling proteins that function at the double-strand break site. We also discuss some plausible ideas that could be considered for future structural approaches to visualize and build a more complete understanding of protein dynamics at the break site.

中文翻译：

---

DNA 双链断裂信号传导的结构见解


基因组完整性受到双链断裂的最大威胁，如果不修复，就会导致癌变或细胞死亡。 DNA损伤产生的细胞产生蛋白质-蛋白质信号相互作用网络，现在被认为是抗癌疗法开发的丰富基础。由于信号蛋白尺寸大且结构域组织复杂，破译信号蛋白的结构一直是一项艰巨的任务。哺乳动物蛋白质表达/纯化和基于冷冻电镜的结构测定的最新进展使我们对这些大型多结构域蛋白质的理解取得了重大进展。这篇综述概述了在双链断裂位点发挥作用的一些关键信号蛋白的结构原理。我们还讨论了一些可能的想法，这些想法可以考虑用于未来的结构方法，以可视化和更全面地了解断裂位点的蛋白质动力学。