Nuclear Deformation Causes DNA Damage by Increasing Replication Stress

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

doi:10.1016/j.cub.2020.11.037

Cited by 117 publications

(101 citation statements)

References 74 publications

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“…As a result, lower lamin A levels promote faster transit through small constrictions requiring nuclear deformation. However, squeezing the nucleus through small confinements can result in DNA damage caused by both the deformation of the nucleus and rupture of nuclear envelope (Irianto et al, 2016a;Raab et al, 2016;Shah et al, 2020). Importantly, mutation or depletion of lamin A/C increases the frequency of nuclear envelope rupture and impairs the ability to efficiently repair and survive rupture events (Denais et al, 2016;Earle et al, 2020;Irianto et al, 2016a;Raab et al, 2016).…”

Section: Discussionmentioning

confidence: 99%

Low lamin A levels enhance confined cell migration and metastatic capacity in breast cancer

Bell

Shah

Zuela-Sopilniak

et al. 2021

Preprint

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Aberrations in nuclear size and shape are commonly used to identify cancerous tissue. However, it remains unclear whether the disturbed nuclear structure directly contributes to the cancer pathology or is merely a consequence of other events occurring during tumorigenesis. Here, we show that highly invasive and proliferative breast cancer cells have lower expression of the nuclear envelope proteins lamin A/C, leading to increased nuclear deformability that permits enhanced cell migration through confined environments that mimic interstitial spaces encountered during metastasis. Importantly, increasing lamin A/C expression in highly invasive breast cancer cells altered expression of numerous other proteins implicated in metastatic progression. Further supporting an important role of lamins in breast cancer metastasis, analysis of lamin levels in human breast tumors revealed a significant association between lower lamin A levels and decreased disease-free survival. These findings suggest that downregulation of lamin A/C may influence both biochemical and physical properties of the cell to promote breast cancer metastatic progression.

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Section: Discussionmentioning

confidence: 99%

Low lamin A levels enhance confined cell migration and metastatic capacity in breast cancer

Bell

Shah

Zuela-Sopilniak

et al. 2021

Preprint

Self Cite

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“…Deformation of the nucleus during confined migration of MDA-MB-231 and BT-549 breast cancer cells or by mechanical compression of static cells can cause DNA damage in the S/G2 phase of the cell cycle without requiring mechanical rupture of the envelope (Shah et al, 2021). The DNA damage is likely due to a stalling of the DNA replication fork.…”

Section: Effect Of Compressive Stress On the Nucleusmentioning

confidence: 99%

Molecular cancer cell responses to solid compressive stress and interstitial fluid pressure

2021

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Alterations to the mechanical properties of the microenvironment are a hallmark of cancer. Elevated mechanical stresses exist in many solid tumors and elicit responses from cancer cells. Uncontrolled growth in confined environments gives rise to elevated solid compressive stress on cancer cells. Recruitment of leaky blood vessels and an absence of functioning lymphatic vessels causes a rise in the interstitial fluid pressure. Here we review the role of the cancer cell cytoskeleton and the nucleus in mediating both the initial and adaptive cancer cell response to these two types of mechanical stresses. We review how these mechanical stresses alter cancer cell functions such as proliferation, apoptosis, and migration.

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“…Importantly, deformation of the nucleus, whether by migration through small pores, direct application of force, or spreading on stiff substrates, has been implicated in the loss of nuclear repair factors and accumulation of DNA damage [ 71 , 72 , 73 , 74 ]. Though increased DNA damage from deformation has not yet been documented in primary liver cells, nuclear deformation is increased in chronic liver diseases, raising the possibility that deformation is a mechanism of oncogenesis [ 61 , 75 ].…”

Section: Mechanically Induced Nuclear Deformation Activates Oncogenic Signaling and Increases Dna Damagementioning

confidence: 99%

Perspective: The Mechanobiology of Hepatocellular Carcinoma

Loneker

Wells

2021

Cancers

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Hepatocellular carcinoma (HCC) is the second most deadly primary cancer in the world and is thus a major global health challenge. HCC primarily develops in patients with an underlying chronic liver disease, the vast majority with advanced cirrhosis, characterized by increased matrix deposition and liver stiffness. Liver stiffness is highly associated with cancer development and poor patient outcome and is measured clinically to assess cancer risk; cirrhotic livers greatly exceed the threshold stiffness shown to alter hepatocyte cell behavior and to increase the malignancy of cancer cells. Recent studies have shown that cirrhotic liver cells have highly irregular nuclear morphologies and that nuclear deformation mediates mechanosensitive signaling. Separate research has shown that nuclear deformation can increase genetic instability and the accumulation of DNA damage in migrating cancer cells. We hypothesize that the mechanical changes associated with chronic liver disease are drivers of oncogenesis, activating mechanosensitive signaling pathways, increasing rates of DNA damage, and ultimately inducing malignant transformation.

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Nuclear Deformation Causes DNA Damage by Increasing Replication Stress

Cited by 117 publications

References 74 publications

Low lamin A levels enhance confined cell migration and metastatic capacity in breast cancer

Low lamin A levels enhance confined cell migration and metastatic capacity in breast cancer

Molecular cancer cell responses to solid compressive stress and interstitial fluid pressure

Perspective: The Mechanobiology of Hepatocellular Carcinoma

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