Nuclear deformation causes DNA damage by increasing replication stress

Shah, Pragya; Cheng, Svea; Hobson, Chad M.; Colville, Marshall J.; Paszek, Matthew J.; Superfine, Richard; Lammerding, Jan

doi:10.1101/2020.06.12.148890

Cited by 19 publications

(31 citation statements)

References 74 publications

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“…Close associations between NE rupture and the loss of lamin A/C and lamin B1 as well as the mutation of nuclear lamins exist in HGPS and cancer (Earle et al, 2020;Penfield et al, 2018). Cancer cells suffer more NE rupture, DNA damage and nuclear deformation through confining space (Denais et al, 2016;Kidiyoor et al, 2020;Shah et al, 2021). The confined migration and compression force increased replication stress and promoted replication fork stalling (Shah et al, 2021).…”

Section: Ne Stressmentioning

confidence: 99%

“…Cancer cells suffer more NE rupture, DNA damage and nuclear deformation through confining space (Denais et al, 2016;Kidiyoor et al, 2020;Shah et al, 2021). The confined migration and compression force increased replication stress and promoted replication fork stalling (Shah et al, 2021). In addition, the ATR defective cells generated NE rupture, perinuclear cGAS (cyclic GMP-AMP synthase) accumulation and aberrant perinuclear chromatin status during interstitial migration or mechanical force loading (Kidiyoor et al, 2020).…”

Section: Ne Stressmentioning

confidence: 99%

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Nuclear envelope integrity, DNA replication, damage repair and genome stability

Zhang

Qin

et al. 2021

GENOME INSTAB. DIS.

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The nuclear envelope (NE) not only shields the genetic material inside the nucleus, maintains the dynamic shapes of nucleus, and regulates nuclear exchange with cytosol, but also participates in DNA replication, damage repair and transcription regulation. The loss of NE integrity, as observed in various diseases, has been shown to cause genome instability as a result of genetic material leaking into the cytoplasm. An underestimated but critically important factor of genome integrity is the role of NE components that involve in DNA replication and damage repair. In this review, we summarize the triggers of NE loss and its cellular consequences by focusing on the interactions between NE components and DNA replication and repair factors. Studies on how NE mediates DNA replication and damage repair could shed light on the diagnosis and treatment of human diseases such as cancer and laminopathy.

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Section: Ne Stressmentioning

confidence: 99%

Section: Ne Stressmentioning

confidence: 99%

Nuclear envelope integrity, DNA replication, damage repair and genome stability

Zhang

Qin

et al. 2021

GENOME INSTAB. DIS.

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“…Through treating the nucleus as an elastic-fluid system wherein the fluid surrounding the chromatin can be squeezed out of the nucleus, their model showed that outflow of mobile repair proteins due to the constricted migration was sufficient to explain the experimental data on increased damage sites [47]. Recent experimental work has shown similarly that nuclear deformation alone can cause increased DNA damage [110]. In their model, nuclear rupture was assumed to merely delay the ability of the repair factors to return to their original locations.…”

Section: Nuclear Blebbing and Rupturementioning

confidence: 99%

Modeling of Cell Nuclear Mechanics: Classes, Components, and Applications

Hobson

Stephens²

2020

Cells

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Cell nuclei are paramount for both cellular function and mechanical stability. These two roles of nuclei are intertwined as altered mechanical properties of nuclei are associated with altered cell behavior and disease. To further understand the mechanical properties of cell nuclei and guide future experiments, many investigators have turned to mechanical modeling. Here, we provide a comprehensive review of mechanical modeling of cell nuclei with an emphasis on the role of the nuclear lamina in hopes of spurring future growth of this field. The goal of this review is to provide an introduction to mechanical modeling techniques, highlight current applications to nuclear mechanics, and give insight into future directions of mechanical modeling. There are three main classes of mechanical models—schematic, continuum mechanics, and molecular dynamics—which provide unique advantages and limitations. Current experimental understanding of the roles of the cytoskeleton, the nuclear lamina, and the chromatin in nuclear mechanics provide the basis for how each component is subsequently treated in mechanical models. Modeling allows us to interpret assay-specific experimental results for key parameters and quantitatively predict emergent behaviors. This is specifically powerful when emergent phenomena, such as lamin-based strain stiffening, can be deduced from complimentary experimental techniques. Modeling differences in force application, geometry, or composition can additionally clarify seemingly conflicting experimental results. Using these approaches, mechanical models have informed our understanding of relevant biological processes such as migration, nuclear blebbing, nuclear rupture, and cell spreading and detachment. There remain many aspects of nuclear mechanics for which additional mechanical modeling could provide immediate insight. Although mechanical modeling of cell nuclei has been employed for over a decade, there are still relatively few models for any given biological phenomenon. This implies that an influx of research into this realm of the field has the potential to dramatically shape both future experiments and our current understanding of nuclear mechanics, function, and disease.

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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 ( Rossi et al, 2008 ; Jeggo et al, 2016 ; Sperka et al, 2012 ; Adams et al, 2015 ). Recent in vitro studies using cancer cell lines, dendritic cells, as well as primary stem cells have shown that migration through micro capillaries or extreme constrictions imparts mechanical stress on nuclei, and this can be a source of DNA damage and genome instability ( Denais et al, 2016 ; Raab et al, 2016 ; Irianto et al, 2017a ; Smith et al, 2019 ; Nader, 2020 ; Shah et al, 2017 ; Shah, 2020 ; Kirby and Lammerding, 2018 ). These studies reveal an assortment of mechanisms by which mechanical stress results in DNA damage.…”

Section: Introductionmentioning

confidence: 99%

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

Sahu

Sridhar

Abnave

et al. 2021

eLife

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Mechanical stress during cell migration may be a previously unappreciated source of genome instability, but the extent to which this happens in any animal in vivo remains unknown. We consider an in vivo system where the adult stem cells of planarian flatworms are required to migrate to a distal wound site. 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 exhibit increased levels of DNA damage. Increased DNA damage levels reduce once stem cells reach the wound site. Stem cells in which DNA damage is induced prior to wounding take longer to initiate migration and migrating stem cell populations are more sensitive to further DNA damage than stationary stem cells. RNAi-mediated knockdown of DNA repair pathway components blocks normal stem cell migration, confirming that active DNA repair pathways are required to allow successful migration to a distal wound site. Together these findings provide evidence that levels of migration-coupled-DNA-damage are significant in adult stem cells and that ongoing migration requires DNA repair mechanisms. Our findings reveal that migration of normal stem cells in vivo represents an unappreciated source of damage, which could be a significant source of mutations in animals during development or during long-term tissue homeostasis.

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Nuclear deformation causes DNA damage by increasing replication stress

Cited by 19 publications

References 74 publications

Nuclear envelope integrity, DNA replication, damage repair and genome stability

Nuclear envelope integrity, DNA replication, damage repair and genome stability

Modeling of Cell Nuclear Mechanics: Classes, Components, and Applications

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

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