DNA damage alters nuclear mechanics through chromatin reorganization

Abstract DNA double-strand breaks drive genomic instability. However, it remains unknown how these processes may affect the biomechanical properties of the nucleus and what role nuclear mechanics play in DNA damage and repair efficiency. Here, we have used Atomic Force Microscopy to investigate nucl...

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Bibliographic Details
Published in:Nucleic acids research 2021-01, Vol.49 (1), p.340-353
Main Authors: dos Santos, Ália, Cook, Alexander W, Gough, Rosemarie E, Schilling, Martin, Olszok, Nora A, Brown, Ian, Wang, Lin, Aaron, Jesse, Martin-Fernandez, Marisa L, Rehfeldt, Florian, Toseland, Christopher P
Format: Article
Language:English
Subjects:
Cell Nucleus - drug effects
Cell Nucleus - ultrastructure
Cells, Cultured
Chromatin - genetics
Chromatin - ultrastructure
Cisplatin - pharmacology
Cross-Linking Reagents - pharmacology
Cytoskeleton - ultrastructure
DNA Breaks, Double-Stranded
DNA Damage
Elasticity
Genome Integrity, Repair and
Genomic Instability - genetics
HeLa Cells
Humans
Mesenchymal Stem Cells - cytology
Mesenchymal Stem Cells - drug effects
Microscopy, Atomic Force
Single Molecule Imaging
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Summary:Abstract DNA double-strand breaks drive genomic instability. However, it remains unknown how these processes may affect the biomechanical properties of the nucleus and what role nuclear mechanics play in DNA damage and repair efficiency. Here, we have used Atomic Force Microscopy to investigate nuclear mechanical changes, arising from externally induced DNA damage. We found that nuclear stiffness is significantly reduced after cisplatin treatment, as a consequence of DNA damage signalling. This softening was linked to global chromatin decondensation, which improves molecular diffusion within the organelle. We propose that this can increase recruitment for repair factors. Interestingly, we also found that reduction of nuclear tension, through cytoskeletal relaxation, has a protective role to the cell and reduces accumulation of DNA damage. Overall, these changes protect against further genomic instability and promote DNA repair. We propose that these processes may underpin the development of drug resistance.
ISSN:0305-1048
1362-4962
DOI:10.1093/nar/gkaa1202