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Trendel, J.* ; Trendel, S.* ; Sha, S.* ; Greulich, F.* ; Goll, S.* ; Wudy, S.I.* ; Kleigrewe, K.* ; Kubicek, S.* ; Uhlenhaut, N.H. ; Kuster, B.*

The human proteome with direct physical access to DNA.

Cell 188, 4424-4440 (2025)
Publ. Version/Full Text Research data DOI PMC
Open Access Hybrid
Creative Commons Lizenzvertrag
In a human cell, DNA is packed with histones, RNA, and chromatin-associated proteins, forming a cohesive gel. At any given moment, only a subset of the proteome has physical access to the DNA and organizes its structure, transcription, replication, repair, and other essential molecular functions. We have developed a "zero-distance" photo-crosslinking approach to quantify proteins in direct contact with DNA in living cells. Collecting DNA interactomes from human breast cancer cells, we present an atlas of over one thousand proteins with physical access to DNA and hundreds of peptide-nucleotide crosslinks pinpointing protein-DNA interfaces with single-amino-acid resolution. Quantitative comparisons of DNA interactomes from differentially treated cells recapitulate the recruitment of key transcription factors as well as DNA repair proteins and uncover fast-acting restrictors of chromatin accessibility on a timescale of minutes. This opens a direct way to explore genomic regulation in a hypothesis-free manner, applicable to many organisms and systems.
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Publication type Article: Journal article
Document type Scientific Article
Keywords Dna-binding Domains ; Dna-binding Proteins ; Dna-interacting Proteome ; Idrs ; Chromatin Proteomics ; Intrinsically Disordered Regions ; Mass Spectrometry ; Nucleotide-peptide Hybrids ; Photo-crosslinking ; Physical Protein-dna Interactions ; Transcription Factors; Intrinsically Disordered Regions; Cross-linking; Photochemical Addition; Peptide Identification; Replication Proteins; Histone Acetylation; Mass-spectrometry; Crystal-structure; Amino-acids; Chromatin
Language english
Publication Year 2025
HGF-reported in Year 2025
ISSN (print) / ISBN 0092-8674
e-ISSN 1097-4172
Journal Cell
Quellenangaben Volume: 188, Issue: 16, Pages: 4424-4440 Article Number: , Supplement: ,
Publisher Cell Press
Publishing Place Cambridge, Mass.
Reviewing status Peer reviewed
Institute(s) Institute of Diabetes and Cancer (IDC)
Institute of Diabetes and Endocrinology (IDE)
POF-Topic(s) 90000 - German Center for Diabetes Research
30202 - Environmental Health
Research field(s) Helmholtz Diabetes Center
PSP Element(s) G-501900-227
G-501900-259
Grants Bavarian Research Foundation
German Research Council (DFG)
DOI 10.1016/j.cell.2025.04.037
WOS ID 001550595100007
Scopus ID 105005869488
PubMed ID 40409270
Erfassungsdatum 2025-05-26
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