DNA Damage Response Assemblies Map (DDRAM)

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 the DDR and their organization into complexes, including constitutive interactions and those responding to genomic insult. 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. This map captures canonical repair mechanisms and proposes new DDR-associated proteins extending to stress, transport, and chromatin functions. We find that protein assemblies closely align with genetic dependencies in processing specific genotoxic agents, and that proteins in multiple assemblies typically act in multiple genotoxin responses. Follow-up by specific DDR readouts implicates 12 new candidates in double-strand-break repair. The DNA Damage Response Assemblies Map is available for interactive visualization and query (ccmi.org/ddram/).