Actomyosin drives cancer cell nuclear dysmorphia and threatens genome stability
| Autor: | Marco Montagner, Karoly Szuhai, Murielle P. Serres, Matthew R. G. Russell, Mark Petronczki, Tohru Takaki, Simon J. Boulton, Michael Howell, Lucy M. Collinson, Erik Sahai, Maël Le Berre |
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| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Genome instability Cell Nucleus Shape DNA damage Nuclear Envelope Science General Physics and Astronomy macromolecular substances Biology General Biochemistry Genetics and Molecular Biology Genomic Instability Article Contractility 03 medical and health sciences Myosin-Light-Chain Phosphatase Neoplasms Protein Phosphatase 1 medicine Humans Actin Genetics Multidisciplinary General Chemistry Actomyosin Cell biology Cell nucleus 030104 developmental biology medicine.anatomical_structure Cancer cell Myosin-light-chain phosphatase HeLa Cells |
| Zdroj: | Nature Communications, Vol 8, Iss 1, Pp 1-13 (2017) Nature Communications, 8 Nature Communications |
| Popis: | Altered nuclear shape is a defining feature of cancer cells. The mechanisms underlying nuclear dysmorphia in cancer remain poorly understood. Here we identify PPP1R12A and PPP1CB, two subunits of the myosin phosphatase complex that antagonizes actomyosin contractility, as proteins safeguarding nuclear integrity. Loss of PPP1R12A or PPP1CB causes nuclear fragmentation, nuclear envelope rupture, nuclear compartment breakdown and genome instability. Pharmacological or genetic inhibition of actomyosin contractility restores nuclear architecture and genome integrity in cells lacking PPP1R12A or PPP1CB. We detect actin filaments at nuclear envelope rupture sites and define the Rho-ROCK pathway as the driver of nuclear damage. Lamin A protects nuclei from the impact of actomyosin activity. Blocking contractility increases nuclear circularity in cultured cancer cells and suppresses deformations of xenograft nuclei in vivo. We conclude that actomyosin contractility is a major determinant of nuclear shape and that unrestrained contractility causes nuclear dysmorphia, nuclear envelope rupture and genome instability. Recent findings suggest that forces acting on the cell nucleus can cause DNA damage, but the mechanisms are unclear. Here Takaki et al. report that actomyosin is a determinant of nuclear shape and that unrestrained contractility elicits nuclear envelope rupture and genome instability in cancer cells. |
| Databáze: | OpenAIRE |
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