Extracellular matrix stiffness determines DNA repair efficiency and cellular sensitivity to genotoxic agents

Min Deng, Jing Lin, Somaira Nowsheen, Tongzheng Liu, Yingchun Zhao, Peter W. Villalta, Delphine Sicard, Daniel J. Tschumperlin, Seung Baek Lee, Jung Jin Kim, Zhenkun Lou

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

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.

Original languageEnglish (US)
Article numbereabb2630
JournalScience Advances
Volume6
Issue number37
DOIs
StatePublished - Sep 2020

Bibliographical note

Funding Information:
Acknowledgments: We thank J. W. Chin (Medical Research Council Laboratory of Molecular Biology, UK), K. Guan (University of California San Diego, CA), and Z. J. Chen (University of Texas Southwestern Medical Center) for providing reagents used in this study. Funding: This study was partially funded by the Fraternal Order of Eagles Cancer Research Fund (to M.D.) grant number FP00089365. Author contributions: M.D. and Z.L. designed and interpreted the experiments and wrote the manuscript. M.D., J.L., T.L., Y.Z., D.S., S.N., S.L., and J.K. performed the experiments. D.J.T. and P.W.V. helped designed the experiments. Competing interests: The authors declare that they have no competing interests. Data and materials availability: All data needed to evaluate the conclusions in the paper are present in the paper and/or the Supplementary Materials. Additional data related to this paper may be requested from the authors.

Funding Information:
We thank J. W. Chin (Medical Research Council Laboratory of Molecular Biology, UK), K. Guan (University of California San Diego, CA), and Z. J. Chen (University of Texas Southwestern Medical Center) for providing reagents used in this study. This study was partially funded by the Fraternal Order of Eagles Cancer Research Fund (to M.D.) grant number FP00089365.

Publisher Copyright:
Copyright © 2020 The Authors, some rights reserved

PubMed: MeSH publication types

  • Journal Article

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