A multi-scale map of protein assemblies in the DNA damage response.
DNA damage response
double-strand break repair
multi-omics
protein assemblies
protein networks
single-strand break repair
systems biology
visualization
Journal
Cell systems
ISSN: 2405-4720
Titre abrégé: Cell Syst
Pays: United States
ID NLM: 101656080
Informations de publication
Date de publication:
21 Jun 2023
21 Jun 2023
Historique:
received:
15
09
2021
revised:
30
01
2023
accepted:
25
04
2023
pmc-release:
21
06
2024
medline:
26
6
2023
pubmed:
24
5
2023
entrez:
23
5
2023
Statut:
ppublish
Résumé
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/).
Identifiants
pubmed: 37220749
pii: S2405-4712(23)00116-3
doi: 10.1016/j.cels.2023.04.007
pmc: PMC10330685
mid: NIHMS1903772
pii:
doi:
Substances chimiques
Chromatin
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
447-463.e8Subventions
Organisme : NCI NIH HHS
ID : R01 CA238061
Pays : United States
Organisme : NCI NIH HHS
ID : F99 CA264422
Pays : United States
Organisme : NIEHS NIH HHS
ID : U01 ES029518
Pays : United States
Organisme : NIEHS NIH HHS
ID : R01 ES014811
Pays : United States
Organisme : NCI NIH HHS
ID : U54 CA274502
Pays : United States
Organisme : NCI NIH HHS
ID : U54 CA209891
Pays : United States
Organisme : NHGRI NIH HHS
ID : U24 HG012107
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA148629
Pays : United States
Organisme : NIH HHS
ID : OT2 OD032742
Pays : United States
Organisme : NCI NIH HHS
ID : T32 CA067754
Pays : United States
Informations de copyright
Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of interests T.I. is co-founder of Data4Cure, Inc., is on the Scientific Advisory Board, and has an equity interest. T.I. is on the Scientific Advisory Board of Ideaya BioSciences, Inc. and has an equity interest. The terms of these arrangements have been reviewed and approved by the University of California San Diego in accordance with its conflict of interest policies. R.W.S. is co-founder of Canal House Biosciences, LLC, is on the Scientific Advisory Board, and has an equity interest. N.J.K. is a shareholder of Tenaya Therapeutics and has received stocks from Maze Therapeutics and Interline Therapeutics; has consulting agreements with the Icahn School of Medicine at Mount Sinai, New York, Maze Therapeutics and Interline Therapeutics. The laboratory of N.J.K. has received research support from Vir Biotechnology and F. Hoffmann-La Roche.
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