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

Anton Kratz, Minkyu Kim, Marcus R. Kelly, Fan Zheng, Christopher A. Koczor, Jianfeng Li, Keiichiro Ono, Yue Qin, Christopher Churas, Jing Chen, Rudolf T. Pillich, Jisoo Park, Maya Modak, Rachel Collier, Kate Licon, Dexter Pratt, Robert W. Sobol, Nevan J. Krogan, Trey Ideker

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

Abstract

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 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 into 109 assemblies. The 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 genotoxins and that proteins in multiple assemblies typically act in multiple genotoxin responses. Follow-up by DDR functional readouts newly implicates 12 assembly members in double-strand-break repair. The DNA damage response assemblies map is available for interactive visualization and query (ccmi.org/ddram/).

Original languageEnglish (US)
Pages (from-to)447-463.e8
JournalCell Systems
Volume14
Issue number6
DOIs
StatePublished - Jun 21 2023

Keywords

  • DNA damage response
  • double-strand break repair
  • multi-omics
  • protein assemblies
  • protein networks
  • single-strand break repair
  • systems biology
  • visualization

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Cell Biology
  • Histology

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