ArticleScience advances2020
Extracellular matrix stiffness determines DNA repair efficiency and cellular sensitivity to genotoxic agents.
Article in Science advances, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 52 papers.
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Who cites it
52 citing papers in PubMed, 83 citations in OpenAlex.
- Mechanosensors Collaborate to Regulate DNA Damage Repair in Hepatocellular Carcinoma.Cancer research · 2026Article
- Hardened ground: ECM stiffness as a unifying biomechanical driver of reproductive stem cell aging.Biogerontology · 2026Review
- Beyond DNA damage: 3D tumor models and the integrin mechanobiology of radioresistance.Journal of experimental & clinical cancer research : CR · 2026Review
- Mechanobiology of the tumor microenvironment: a review of therapeutic interactions and in vitro elasticity measurement techniques.Journal of biomedical science · 2026Review
- Toward More Translational Tumor Models: Breast dECM-Based 3D Systems Capture Native Microenvironmental Cues.Bioengineering (Basel, Switzerland) · 2026Article
- IQGAP3 bridges matrix stiffness with glioma stem cell maintenance and radioresistance by stabilizing SOX2.Nature communications · 2026Article
- Cancer-associated fibroblasts regulate DNA repair in pancreatic cancer through NDRG1-mediated R-loop processing.Nature cell biology · 2026Article
- Statistical models to characterize colon tumor stiffness heterogeneity through representative atomic force microscopy maps.Scientific reports · 2026Article
- Combination of PARP and KRASNature communications · 2026Article
- Three-dimensional-bioprinted stiff matrix triggers PDAC radioresistance through histone H3 lysine 18 lactylation (H3K18la) potentiates RAD51 activation.Regenerative biomaterials · 2026Article
- The relationship between DNA damage and repair and the occurrence and development of disease.Frontiers in genetics · 2026Review
- Drug resistance in cancer: molecular mechanisms and emerging treatment strategies.Molecular biomedicine · 2025Review
- Extending the microdosimetry gamma model (MGM) to estimate induced DNA damage and its complexity at macroscopic scale by protons and helium ions.Physics in medicine and biology · 2025Article
- Decoding the ubiquitin network: molecular mechanisms and therapeutic vulnerabilities for precision radio-sensitization in cancer.Molecular cancer · 2025Review
- Interfacial Stress Regulates Plasticity and Drug Resistance at the Breast Cancer-Host Interface.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025Article
- Matrix stiffness regulates glucose-6-phosphate dehydrogenase expression to mediate sorafenib resistance in hepatocellular carcinoma through the ITGB1-PI3K/AKT pathway.Cell death & disease · 2025Article
- Identification of DNA damage and repair gene-related markers in pancreatic ductal adenocarcinoma by single-cell and bulk RNA sequencing.Discover oncology · 2025Article
- Aberrant Activation of Wound-Healing Programs within the Metastatic Niche Facilitates Lung Colonization by Osteosarcoma Cells.Clinical cancer research : an official journal of the American Association for Cancer Research · 2025Article
- Matrix stiffness boosts PDAC chemoresistance via SCD1-dependent lipid metabolic reprogramming.Regenerative biomaterials · 2025Article
- Hotspots and frontiers of the relationship between gastric cancer and cancer-associated fibroblasts: a bibliometric analysis.Frontiers in oncology · 2025Article
Corrections and comments
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Authors and funding
11 authors at 6 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
DNA double-strand breaks (DSBs) are highly toxic lesions that can drive genetic instability. These lesions also contribute to the efficacy of radiotherapy and many cancer chemotherapeutics. DNA repair efficiency is regulated by both intracellular and extracellular chemical signals. However, it is largely unknown whether this process is regulated by physical stimuli such as extracellular mechanical signals. Here, we report that DSB repair is regulated by extracellular mechanical signals. Low extracellular matrix (ECM) stiffness impairs DSB repair and renders cells sensitive to genotoxic agents. Mechanistically, we found that the MAP4K4/6/7 kinases are activated and phosphorylate ubiquitin in cells at low stiffness. Phosphorylated ubiquitin impairs RNF8-mediated ubiquitin signaling at DSB sites, leading to DSB repair deficiency. Our results thus demonstrate that ECM stiffness regulates DSB repair efficiency and genotoxic sensitivity through MAP4K4/6/7 kinase-mediated ubiquitin phosphorylation, providing a previously unidentified regulation in DSB-induced ubiquitin signaling.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.