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Nat Commun. 2017 Jul 24;8:16013. doi: 10.1038/ncomms16013.

Actomyosin drives cancer cell nuclear dysmorphia and threatens genome stability.

Author information

1
Cell Division and Aneuploidy Laboratory, Cancer Research UK London Research Institute, Clare Hall Laboratories, South Mimms, Hertfordshire EN6 3LD, UK.
2
DSB Repair Metabolism Laboratory, The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK.
3
Tumour Cell Biology Laboratory, The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK.
4
MRC Laboratory for Molecular Cell Biology, UCL, Gower Street, London WC1E 6BT, UK.
5
Institut Curie, PSL Research University, CNRS, UMR 144, F-75005 Paris, France.
6
Electron Microscopy Group, The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK.
7
Department of Molecular Cell Biology, LUMC, Einthovenweg 20, 2333 ZC Leiden, The Netherlands.
8
High Throughput Screening Laboratory, The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK.
9
Boehringer Ingelheim RCV GmbH &Co KG, Dr Boehringer Gasse 5-11, A-1121 Vienna, Austria.

Abstract

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.

PMID:
28737169
PMCID:
PMC5527285
DOI:
10.1038/ncomms16013
[Indexed for MEDLINE]
Free PMC Article

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