Bursting the Bubble – Nuclear Envelope Rupture as a Path to Genomic Instability?

Shah, Pragya; Wolf, Katarina; Lammerding, Jan

doi:10.1016/j.tcb.2017.02.008

Cited by 106 publications

(105 citation statements)

References 64 publications

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“…The precise mechanisms by which NE damage and NE rupture cause DNA damage and cell death remains to be elucidated. The DNA damage could arise from exposure of genomic DNA to cytoplasmic nucleases following NE rupture, or nuclear exclusion and efflux of DNA repair factors, as previously discussed in the context of confined cell migration [75][76][77] . The close association of DNA damage with NE defects in our studies (Suppl.…”

Section: Discussionmentioning

confidence: 99%

Mutant lamins cause nuclear envelope rupture and DNA damage in skeletal muscle cells

Earle

Kirby

Fedorchak

et al. 2018

Preprint

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Mutations in the human LMNA gene, which encodes the nuclear envelope proteins lamins A and C, cause autosomal dominant Emery-Dreifuss muscular dystrophy, congenital muscular dystrophy, limb-girdle muscular dystrophy, and other diseases collectively known as laminopathies. The molecular mechanisms responsible for these diseases remain incompletely understood, but the muscle-specific defects suggest that mutations may render nuclei more susceptible to mechanical stress. Using three mouse models of muscle laminopathies, we found that Lmna mutations caused extensive nuclear envelope damage, consisting of chromatin protrusions and transient rupture of the nuclear envelope, in skeletal muscle cells in vitro and in vivo. The nuclear envelope damage was associated with progressive DNA damage, activation of DNA damage response pathways, and reduced viability. Intriguingly, nuclear envelope damage resulted from nuclear movement in maturing skeletal muscle cells, rather than actomyosin contractility, and was reversed by either depletion of kinesin-1 or stabilization of microtubules. Depletion of kinesin-1 also rescued DNA damage, indicating that DNA damage is the result of nuclear envelope damage. The extent of nuclear envelope damage and DNA damage in the different Lmna mouse models strongly correlated with the disease onset and severity in vivo, and inducing DNA damage in wild-type muscle cells was sufficient to phenocopy the reduced cell viability of lamin A/C-deficient muscle cells, suggesting a causative role of DNA damage in disease pathogenesis. Corroborating the mouse model data, muscle biopsies from patients with LMNA associated muscular dystrophy similarly revealed significant DNA damage compared to age-matched controls, particularly in severe cases of the disease. Taken together, these findings point to a new and important role of DNA damage as a pathogenic contributor for these skeletal muscle diseases.

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Section: Discussionmentioning

confidence: 99%

Mutant lamins cause nuclear envelope rupture and DNA damage in skeletal muscle cells

Earle

Kirby

Fedorchak

et al. 2018

Preprint

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“…We know that efficient DNA repair mechanisms to counteract the effects of replicative stress and other sources of damage are central to avoiding both premature ageing and cancer [11][12][13][14]. Recent in vitro studies using cancer cell lines and dendritic cells have shown that migration through micro capillaries imparts mechanical stresses on nuclei, and this can be a source of genome instability [1,2,[15][16][17]. If migrating cells in vivo, in particular stem cells, experience genome instability this has a number of broad implications for metazoan development and homeostasis.…”

Section: Introductionmentioning

confidence: 99%

Ongoing repair of migration-coupled DNA damage allows stem cells to reach wound sites

Sahu

Sridhar

Abnave

et al. 2019

Preprint

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The impact of mechanical stress during cell migration may be a previously unappreciated source of genome instability [1][2][3], but to what extent this happens in vivo remains unknown. Here we consider an in vivo system where the adult stem cells of planarian flatworms are required to migrate to a distal wound site [4]. We observe a relationship between adult stem cell migration and ongoing DNA damage and repair during tissue regeneration. Migrating planarian stem cells undergo changes in nuclear shape and increased levels of DNA damage. Increased DNA damage levels resolve once stem cells reach the wound site and stop migrating. Stem cells in which DNA damage is induced prior to wounding take longer to initiate migration suggesting migration activity is sensitive to DNA damage. Migrating stem cells populations are more sensitive to further DNA damage than stationary stem cells, providing evidence that levels of migration-coupled-DNA-damage (MCDD) are significant. RNAi mediated knockdown of DNA repair pathway components blocks normal stem cell migration, confirming that DNA repair pathways are required to allow successful migration to a distal wound site. Together these lines of evidence demonstrate that migration leans to DNA damage in vivo and requires DNA repair mechanisms. Our findings reveal that migration of stem cells represents an unappreciated source of damage, that could be a significant source of mutations in animals during development or during long term tissue homeostasis. Gene cloning and RNAiThe sequences of S. mediterranea RAD51 and BRCA2 were described previously.Planarian DDR genes were identified by BLAST searches against the the Planmine database, leading to the identification of full-length mRNA transcripts (Smed-ATR-dd_Smed_v6_8754_0_1, Smed PARP1-dd_Smed_v6_10338_0_1, Smed PARP2-dd_Smed_v6_6154_0_1, SmedPARP3-dd_Smed_v6_2611_0_1,

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“…Metastasizing cancer cells that encounter tight interstitial spaces are particularly prone to transient NE rupture. This process is viewed as a new mechanism dependent on confinement that promotes genomic instability and tumor progression (Calero-Cuenca et al, 2018;Shah et al, 2017). Therefore, such a mechanism could be an important part of the tumor-promoting functions of Par3.…”

Section: Discussionmentioning

confidence: 99%

Adenoviral protein E4orf4 interacts with the polarity protein Par3 to induce nuclear rupture and tumor cell death

Dziengelewski

Rodrigue

Caillier

et al. 2020

Journal of Cell Biology

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The tumor cell–selective killing activity of the adenovirus type 2 early region 4 ORF4 (E4orf4) protein is poorly defined at the molecular level. Here, we show that the tumoricidal effect of E4orf4 is typified by changes in nuclear dynamics that depend on its interaction with the polarity protein Par3 and actomyosin contractility. Mechanistically, E4orf4 induced a high incidence of nuclear bleb formation and repetitive nuclear ruptures, which promoted nuclear efflux of E4orf4 and loss of nuclear integrity. This process was regulated by nucleocytoskeletal connections, Par3 clustering proximal to nuclear lamina folds, and retrograde movement of actin bundles that correlated with nuclear ruptures. Significantly, Par3 also regulated the incidence of spontaneous nuclear ruptures facilitated by the downmodulation of lamins. This work uncovered a novel role for Par3 in controlling the actin-dependent forces acting on the nuclear envelope to remodel nuclear shape, which might be a defining feature of tumor cells that is harnessed by E4orf4.

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Bursting the Bubble – Nuclear Envelope Rupture as a Path to Genomic Instability?

Cited by 106 publications

References 64 publications

Mutant lamins cause nuclear envelope rupture and DNA damage in skeletal muscle cells

Mutant lamins cause nuclear envelope rupture and DNA damage in skeletal muscle cells

Ongoing repair of migration-coupled DNA damage allows stem cells to reach wound sites

Adenoviral protein E4orf4 interacts with the polarity protein Par3 to induce nuclear rupture and tumor cell death

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