DDRAMDNA Damage Response Assemblies Map

DDRAM - DNA Damage Response Assemblies Map

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 specific DDR readouts, implicating twelve new proteins in double-strand-break repair. The DNA Damage Response Assemblies Map is available for interactive visualization and query ccmi.org/ddram/.

The HiView web application (https://github.com/idekerlab/hiview/tree/ddram-revise) is an interactive visualization tool which supports exploration of the DDRAM network and any similar hierarchical models. HiView allows the user to (1) interactively zoom across many scales in the model, from an expansive view of the entire hierarchy to more focused views of particular subsystems; (2) browse the network data supporting the inference of each subsystem; and (3) search genes and subsystems based on their names or metadata.

NDEx, the Network Data Exchange (www.ndexbio.org, Pratt et. al. 2017 DOI: 10.1158/0008-5472.CAN-17-0606), is an online commons for biological networks where networks of many types and formats can be shared, accessed, and stored by users and applications. NDEx is tightly integrated with Cytoscape (https://cytoscape.org/), and the DDRAM network can be downloaded to Cytoscape by clicking the “Open in Cytoscape” button at the bottom-right of the web page.

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