Genome-wide DDR protein Association Score (DAS) network

The DNA damage response (DDR) ensures error-free DNA replication and transcription and is disrupted in numerous diseases. An ongoing challenge is to determine the proteins orchestrating DDR and their organization into complexes, including constitutive interactions and those induced by genomic insults. Here we use multi-conditional network analysis to systematically map DDR assemblies at multiple scales. Affinity purifications of 21 DDR proteins, with/without genotoxin exposure, are combined with multi-omics data to reveal a hierarchical organization of 605 proteins in 109 assemblies. Assemblies capture canonical repair mechanisms and propose new DDR-associated proteins extending to stress, transport, and chromatin functions. We find significant associations between protein assemblies and genetic dependencies in processing different genotoxic agents and that multiple-assembly proteins can act pleiotropically in multiple-agent responses. Protein assignments are further supported by specif..., ,

DNA损伤应答（DNA damage response, DDR）可确保DNA复制与转录的精准无误，且在诸多疾病中该通路均发生紊乱。当前长期存在的核心挑战在于，明确调控DDR的蛋白质及其复合物组装形式，包括组成型相互作用与基因组损伤诱导产生的相互作用。本研究采用多条件网络分析方法，在多尺度下系统绘制DDR组装体的图谱。我们对21种DDR蛋白在是否暴露于基因毒素的条件下开展亲和纯化实验，并结合多组学数据，揭示了109个组装体中605种蛋白质的层级组织模式。该图谱涵盖了经典的DNA修复通路，并鉴定出一批新的DDR相关蛋白，其功能覆盖应激响应、物质转运及染色质调控等多个领域。我们发现，蛋白质组装体与不同基因毒性试剂处理过程中的遗传依赖特征之间存在显著关联，且多组装体蛋白可在多种基因毒性试剂的应答过程中发挥多效性功能。蛋白质的功能归属进一步得到了[原文此处内容截断]的支持。