Abstract
The nuclear envelope is a protective barrier for the genome and a mechanotransduction interface between cytoplasm and nucleus, whose malfunction disrupts nucleocytoplasmic transport, compromises DNA repair, accelerates telomere shortening, and promotes genomic instability. Mechanisms governing nuclear envelope remodeling and maintenance in interphase and post-mitotic cells remain poorly understood. Here, we report a role for dynamins, a family of essential brain-enriched membrane- and microtubule-binding GTPases, in preserving nuclear envelope and genomic homeostasis. Cells lacking dynamins exhibit nuclear envelope dysmorphisms, including buds with long narrow necks where damaged DNA frequently accumulates. These cells also show impaired autophagic clearance, reduced levels of key DNA repair proteins, and aberrant microtubules. Nocodazole treatment restores nuclear morphology and reduces DNA damage. Collectively, the data reveal that dynamins promote nuclear envelope homeostasis and removal of damaged DNA via their GTPase activity and interaction with microtubules, providing insights into mechanisms that uphold genome stability and counteract aging-related pathologies.
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Key primary and all secondary data are included in the paper and Supplementary Information file, Source data, as well as the reporting summary. The newly generated constructs, and additional primary data (a part of still ongoing collaborative study) are available from the corresponding author. Source data are provided with this paper.
References
Gruenbaum, Y. & Foisner, R. Lamins: nuclear intermediate filament proteins with fundamental functions in nuclear mechanics and genome regulation. Annu. Rev. Biochem. 84, 131–164 (2015).
Kalukula, Y., Stephens, A. D., Lammerding, J. & Gabriele, S. Mechanics and functional consequences of nuclear deformations. Nat. Rev. Mol. Cell Biol. 23, 583–602 (2022).
Shah, P., Wolf, K. & Lammerding, J. Bursting the bubble—nuclear envelope rupture as a path to genomic instability? Trends Cell Biol. 27, 546–555 (2017).
Pathak, R. U., Soujanya, M. & Mishra, R. K. Deterioration of nuclear morphology and architecture: a hallmark of senescence and aging. Ageing Res. Rev. 67, 101264 (2021).
Karoutas, A. & Akhtar, A. Functional mechanisms and abnormalities of the nuclear lamina. Nat. Cell Biol. 23, 116–126 (2021).
Shpetner, H. S. & Vallee, R. B. Identification of dynamin, a novel mechanochemical enzyme that mediates interactions between microtubules. Cell 59, 421–432 (1989).
Shpetner, H. S. & Vallee, R. B. Dynamin is a GTPase stimulated to high levels of activity by microtubules. Nature 355, 733–735 (1992).
Scaife, R. & Margolis, R. L. Biochemical and immunochemical analysis of rat brain dynamin interaction with microtubules and organelles in vivo and in vitro. J. Cell Biol. 111, 3023–3033 (1990).
Maeda, K., Nakata, T., Noda, Y., Sato-Yoshitake, R. & Hirokawa, N. Interaction of dynamin with microtubules: its structure and GTPase activity investigated by using highly purified dynamin. Mol. Biol. Cell 3, 1181–1194 (1992).
Takei, K., McPherson, P. S., Schmid, S. L. & De Camilli, P. Tubular membrane invaginations coated by dynamin rings are induced by GTP-gamma S in nerve terminals. Nature 374, 186–190 (1995).
Ferguson, S. M. & De Camilli, P. Dynamin, a membrane-remodelling GTPase. Nat. Rev. Mol. Cell Biol. 13, 75–88 (2012).
Thompson, H. M., Cao, H., Chen, J., Euteneuer, U. & McNiven, M. A. Dynamin 2 binds gamma-tubulin and participates in centrosome cohesion. Nat. Cell Biol. 6, 335–342 (2004).
Tanabe, K. & Takei, K. Dynamic instability of microtubules requires dynamin 2 and is impaired in a Charcot-Marie-Tooth mutant. J. Cell Biol. 185, 939–948 (2009).
Cao, H., Garcia, F. & McNiven, M. A. Differential distribution of dynamin isoforms in mammalian cells. Mol. Biol. Cell 9, 2595–2609 (1998).
Herskovits, J. S., Burgess, C. C., Obar, R. A. & Vallee, R. B. Effects of mutant rat dynamin on endocytosis. J. Cell Biol. 122, 565–578 (1993).
Kar, U. P., Dey, H. & Rahaman, A. Cardiolipin targets a dynamin-related protein to the nuclear membrane. eLife 10, e64416 (2021).
Mannino, P. J. et al. Quantitative ultrastructural timeline of nuclear autophagy reveals a role for dynamin-like protein 1 at the nuclear envelope. Nat. Cell Biol. 27, 464–476 (2025).
Papandreou, M. E., Konstantinidis, G. & Tavernarakis, N. Nucleophagy delays aging and preserves germline immortality. Nat. Aging 3, 34–46 (2023).
Fonseca, T. B., Sánchez-Guerrero, Á, Milosevic, I. & Raimundo, N. Mitochondrial fission requires DRP1 but not dynamins. Nature 570, E34–E42 (2019).
Park, R. J. et al. Dynamin triple knockout cells reveal off-target effects of commonly used dynamin inhibitors. J. Cell Sci. 126, 5305–5312 (2013).
Janssen, A. F. J., Breusegem, S. Y. & Larrieu, D. Current methods and pipelines for image-based quantitation of nuclear shape and nuclear envelope abnormalities. Cells 11, 347 (2022).
Goldman, R. D. et al. Accumulation of mutant lamin A causes progressive changes in nuclear architecture in Hutchinson-Gilford progeria syndrome. Proc. Natl. Acad. Sci. USA 101, 8963–8968 (2004).
Scaffidi, P. & Misteli, T. Lamin A-dependent nuclear defects in human aging. Science 312, 1059–1063 (2006).
Lattanzi, G. et al. Lamins are rapamycin targets that impact human longevity: a study in centenarians. J. Cell Sci. 127, 147–157 (2014).
Matias, I. et al. Loss of lamin-B1 and defective nuclear morphology are hallmarks of astrocyte senescence in vitro and in the aging human hippocampus. Aging Cell 21, e13521 (2022).
Ferreira-Marques, M. et al. Ghrelin delays premature aging in Hutchinson-Gilford progeria syndrome. Aging Cell 22, e13983 (2023).
De Silva, N. S. et al. Nuclear envelope disruption triggers hallmarks of aging in lung alveolar macrophages. Nat. Aging 3, 1251–1268 (2023).
Catarinella, G. et al. SerpinE1 drives a cell-autonomous pathogenic signaling in Hutchinson-Gilford progeria syndrome. Cell Death Dis. 13, 737 (2022).
Sundborger, A. C. et al. A dynamin mutant defines a superconstricted prefission state. Cell Rep. 8, 734–742 (2014).
Ramachandran, R. et al. The dynamin middle domain is critical for tetramerization and higher-order self-assembly. EMBO J. 26, 559–566 (2007).
Macia, E. et al. Dynasore, a cell-permeable inhibitor of dynamin. Dev. Cell 10, 839–850 (2006).
Ariotti, N. et al. Ultrastructural localisation of protein interactions using conditionally stable nanobodies. PLoS Biol. 16, e2005473 (2018).
Schulze, R. J. et al. Lipid droplet breakdown requires dynamin 2 for vesiculation of autolysosomal tubules in hepatocytes. J. Cell Biol. 203, 315–326 (2013).
Freund, A., Laberge, R. M., Demaria, M. & Campisi, J. Lamin B1 loss is a senescence-associated biomarker. Mol. Biol. Cell 23, 2066–2075 (2012).
Kang, S. M. et al. Progerinin, an optimized progerin-lamin A binding inhibitor, ameliorates premature senescence phenotypes of Hutchinson-Gilford progeria syndrome. Commun. Biol. 4, 5 (2021).
Berger, C. et al. Cryo-electron tomography on focused ion beam lamellae transforms structural cell biology. Nat. Methods 20, 499–511 (2023).
Lascaux, P. et al. TEX264 drives selective autophagy of DNA lesions to promote DNA repair and cell survival. Cell, https://doi.org/10.1016/j.cell.2024.08.020 (2024).
Hagen, C. et al. Structural basis of vesicle formation at the inner nuclear membrane. Cell 163, 1692–1701 (2015).
De Vos, W. H. et al. Repetitive disruptions of the nuclear envelope invoke temporary loss of cellular compartmentalization in laminopathies. Hum. Mol. Genet. 20, 4175–4186 (2011).
Vargas, J. D., Hatch, E. M., Anderson, D. J. & Hetzer, M. W. Transient nuclear envelope rupturing during interphase in human cancer cells. Nucleus 3, 88–100 (2012).
Karoutas, A. et al. The NSL complex maintains nuclear architecture stability via lamin A/C acetylation. Nat. Cell Biol. 21, 1248–1260 (2019).
Gesson, K. et al. A-type lamins bind both hetero- and euchromatin, the latter being regulated by lamina-associated polypeptide 2 alpha. Genome Res. 26, 462–473 (2016).
Rogakou, E. P., Pilch, D. R., Orr, A. H., Ivanova, V. S. & Bonner, W. M. DNA double-stranded breaks induce histone H2AX phosphorylation on serine 139. J. Biol. Chem. 273, 5858–5868 (1998).
Wang, B., Matsuoka, S., Carpenter, P. & Elledge, S. 53BP1, a mediator of the DNA damage checkpoint. Science 298, 1435–1438 (2002).
Singh, N. P., McCoy, M. T., Tice, R. R. & Schneider, E. L. A simple technique for quantitation of low levels of DNA damage in individual cells. Exp. Cell Res. 175, 184–191 (1988).
Bakkenist, C. J. & Kastan, M. B. DNA damage activates ATM through intermolecular autophosphorylation and dimer dissociation. Nature 421, 499–506 (2003).
Chen, X., Paudyal, S. C., Chin, R. I. & You, Z. PCNA promotes processive DNA end resection by Exo1. Nucleic Acids Res. 41, 9325–9338 (2013).
Chernikova, S. B. et al. Dynamin impacts homology-directed repair and breast cancer response to chemotherapy. J. Clin. Investig. 128, 5307–5321 (2018).
Bailly, C. Irinotecan: 25 years of cancer treatment. Pharmacol. Res. 148, 104398 (2019).
Thomas, A. & Pommier, Y. Targeting topoisomerase I in the era of precision medicine. Clin. Cancer Res. 25, 6581–6589 (2019).
Burute, M. & Kapitein, L. C. Cellular logistics: unraveling the interplay between microtubule organization and intracellular transport. Annu. Rev. Cell Dev. Biol. 35, 29–54 (2019).
Lottersberger, F., Karssemeijer, R. A., Dimitrova, N. & de Lange, T. 53BP1 and the LINC complex promote microtubule-dependent DSB mobility and DNA repair. Cell 163, 880–893 (2015).
Shokrollahi, M. et al. DNA double-strand break-capturing nuclear envelope tubules drive DNA repair. Nat. Struct. Mol. Biol. 31, 1319–1330 (2024).
Vasquez, R. J., Howell, B., Yvon, A. M., Wadsworth, P. & Cassimeris, L. Nanomolar concentrations of nocodazole alter microtubule dynamic instability in vivo and in vitro. Mol. Biol. Cell 8, 973–985 (1997).
Chen, J. G. & Horwitz, S. B. Differential mitotic responses to microtubule-stabilizing and -destabilizing drugs. Cancer Res. 62, 1935–1938 (2002).
Wu, Y. et al. A dynamin 1-, dynamin 3- and clathrin-independent pathway of synaptic vesicle recycling mediated by bulk endocytosis. Elife 3, e01621 (2014).
Lamm, N., Rogers, S. & Cesare, A. J. Chromatin mobility and relocation in DNA repair. Trends Cell Biol. 31, 843–855 (2021).
Wang, Y. et al. Autophagy regulates chromatin ubiquitination in DNA damage response through elimination of SQSTM1/p62. Mol. Cell 63, 34–48 (2016).
Qiang, L. et al. Autophagy positively regulates DNA damage recognition by nucleotide excision repair. Autophagy 12, 357–368 (2016).
Dou, Z. et al. Autophagy mediates degradation of nuclear lamina. Nature 527, 105–109 (2015).
Karantza-Wadsworth, V. et al. Autophagy mitigates metabolic stress and genome damage in mammary tumorigenesis. Genes Dev. 21, 1621–1635 (2007).
Liu, E. Y. et al. Loss of autophagy causes a synthetic lethal deficiency in DNA repair. Proc. Natl. Acad. Sci. USA 112, 773–778 (2015).
Mathew, R. et al. Autophagy suppresses tumor progression by limiting chromosomal instability. Genes Dev. 21, 1367–1381 (2007).
Herve, S. et al. Chromosome mis-segregation triggers cell cycle arrest through a mechanosensitive nuclear envelope checkpoint. Nat. Cell Biol. 27, 73–86 (2025).
Luithle, N. et al. Torsin ATPases influence chromatin interaction of the Torsin regulator LAP1. eLife 9, e63614 (2020).
Nabbi, A. & Riabowol, K. Rapid isolation of nuclei from cells in vitro. Cold Spring Harb. Protoc. 2015, 769–772 (2015).
Gowrisankaran, S. et al. Endophilin-A coordinates priming and fusion of neurosecretory vesicles via intersectin. Nat. Commun. 11, 1266 (2020).
Aveleira, C. A. et al. Neuropeptide Y stimulates autophagy in hypothalamic neurons. Proc. Natl. Acad. Sci. USA 112, E1642–E1651 (2015).
Gyori, B. M., Venkatachalam, G., Thiagarajan, P. S., Hsu, D. & Clement, M. V. OpenComet: an automated tool for comet assay image analysis. Redox Biol. 2, 457–465 (2014).
Olive, P. L., Banáth, J. P. & Durand, R. E. Heterogeneity in radiation-induced DNA damage and repair in tumor and normal cells measured using the “comet” assay. Radiat. Res. 122, 86–94 (1990).
Johnson, E., Seiradake, E. & Jones, E. Y. Correlative in-resin super-resolution and electron microscopy using standard fluorescent proteins. Sci. Rep. 5, 9583 (2015).
Eisenstein, F. et al. Parallel cryo electron tomography on in situ lamellae. Nat. Methods 20, 131–138 (2023).
Rohou, A. & Grigorieff, N. CTFFIND4: fast and accurate defocus estimation from electron micrographs. J. Struct. Biol. 192, 216–221 (2015).
Zheng, S. et al. AreTomo: an integrated software package for automated marker-free, motion-corrected cryo-electron tomographic alignment and reconstruction. J. Struct. Biol. X 6, 100068 (2022).
Buchholz, T.-O. et al. Content-aware image restoration for electron microscopy. in (eds Müller-Reichert, T. & Pigino, G.) Methods in Cell Biology, 277–289 (Academic Press, 2019).
Lamm, L. et al. MemBrain: a deep learning-aided pipeline for detection of membrane proteins in Cryo-electron tomograms. Comput. Methods Prog. Biomed. 224, 106990 (2022).
Kremer, J. R., Mastronarde, D. N. & McIntosh, J. R. Computer visualization of three-dimensional image data using IMOD. J. Struct. Biol. 116, 71–76 (1996).
Ermel, U. H., Arghittu, S. M. & Frangakis, A. S. ArtiaX: an electron tomography toolbox for the interactive handling of sub-tomograms in UCSF ChimeraX. Protein Sci. 31, e4472 (2022).
Frangakis, A. S. It’s noisy out there! A review of denoising techniques in cryo-electron tomography. J. Struct. Biol. 213, 107804 (2021).
Pettersen, E. F. et al. UCSF ChimeraX: structure visualization for researchers, educators, and developers. Protein Sci. 30, 70–82 (2021).
Acknowledgements
We thank Pietro De Camilli (Yale University) for providing dynamin conditional cells and plasmids, and K. Zhang and Dr R. Dias for assistance with data analysis. This work was supported by Wellcome Trust Investigator Award in Science (224361/Z/21/Z), La Caixa Foundation (HR22-00854) and the John Black Foundation awarded to I.M., as well as the EU-Horizon 2020 MIA-Portugal teaming grant (857524). N.R. received support from FCT ERC-Portugal and Four Diamonds Paediatric Cancer Research Funds. K.R. received support from the Medical Research Council (MRC) programme (MR/X006409/1), Breast Cancer Now (2022.11PR1570), Ministry of Education Start-Up Grant (023917-00001, Singapore), and the Toh Kian Chui Distinguished Professorship Award. P.L. was funded by the Luxembourg National Fund (14548187), and M.L.C. was supported by a Wellcome Trust DPhil studentship. We acknowledge the Oxford Particle Imaging Centre for access to electron microscopy equipment, and computational resources were supported by the Wellcome Trust Core Award (203141/Z/16/Z) with additional support from the NIHR Oxford BRC. Molecular graphics and analyses were performed using UCSF Chimera, developed by the Resource for Biocomputing, Visualization, and Informatics at the University of California San Francisco, with support from NIH P41-GM103311. The views expressed are those of the authors and do not necessarily reflect those of the NHS, the NIHR, or the Department of Health.
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Conceptualization I.M. and C.A.; Experimentation C.A., T.M., L.C., R.G., F.W., N.R., and I.M.; Analysis C.A., T.M., L.C., M.L.C., I.My., J.B., N.R., and I.M.; Resources: I.M., N.R., K.R., P.L., A.C.R., and C.S.; Funding: N.R., K.R., and I.M.; Manuscript, figure preparation and revision: I.M., N.R., C.A., and T.M. (all coauthors contributed to the final manuscript).
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Aveleira, C., Martial, T., Carrique, L. et al. Dynamins maintain nuclear envelope homeostasis and genome stability. Nat Commun (2026). https://doi.org/10.1038/s41467-025-68130-4
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DOI: https://doi.org/10.1038/s41467-025-68130-4
