A multi-scale map of protein assemblies in the DNA damage response

Area of Science:

• Molecular Biology
• Genetics
• Systems Biology

Background:

• The DNA damage response (DDR) is crucial for maintaining genomic integrity during DNA replication and transcription.
• Dysregulation of DDR pathways is implicated in various diseases, highlighting the need to understand its molecular mechanisms.
• Identifying protein complexes and their dynamic organization within the DDR remains a significant challenge.

Purpose of the Study:

• To systematically map protein assemblies involved in the DNA damage response (DDR) at multiple scales.
• To elucidate the hierarchical organization of DDR proteins and their interactions in response to genomic insult.
• To identify novel proteins associated with DDR pathways and their functional roles.

Main Methods:

• Employed multi-conditional network analysis to map DDR assemblies.
• Utilized affinity purification of 21 DDR proteins under varying genotoxin exposure conditions.
• Integrated multi-omics data to identify and characterize 109 protein assemblies comprising 605 proteins.

Main Results:

• Generated a comprehensive map of 109 hierarchical DDR protein assemblies involving 605 proteins.
• Identified canonical repair mechanisms and proposed new DDR-associated proteins with roles in stress, transport, and chromatin.
• Demonstrated alignment between protein assembly composition, genetic dependencies for genotoxin processing, and functional roles in double-strand-break repair.

Conclusions:

• The study provides a detailed map of DDR protein organization, revealing hierarchical structures and dynamic interactions.
• The findings expand the known repertoire of DDR proteins and their functional associations.
• The DDR assemblies map serves as a valuable resource for understanding genomic stability and disease mechanisms.