Actomyosin drives cancer cell nuclear dysmorphia and threatens genome stability

Tohru Takaki,Michael Howell,Simon J Boulton,Erik Sahai,Murielle P Serres,Lucy Collinson,Marco Montagner,Mark Petronczki,Karoly Szuhai,Matt Russell,Maël Le Berre

doi:10.1038/ncomms16013

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.

Highlights

Altered nuclear shape is a defining feature of cancer cells
PPP1R12A is a regulator of PPP1CB, one of three enzymatic protein phosphatase 1 (PP1) genes encoded in the human genome
Expression of siRNA-resistant transgenes encoding the phosphatase subunits PPP1R12A and PPP1CB restored normal nuclear shape upon depletion of the endogenous counterparts (Supplementary Fig. 2). These results demonstrate that the phosphatase enzyme PPP1CB and its regulator PPP1R12A are required to maintain normal nuclear morphology in cultured human cells

Summary

Introduction

Altered nuclear shape is a defining feature of cancer cells. The mechanisms underlying nuclear dysmorphia in cancer remain poorly understood. We identify PPP1R12A and PPP1CB, two subunits of the myosin phosphatase complex that antagonizes actomyosin contractility, as proteins safeguarding nuclear integrity. 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. Nuclear dysmorphia has been used for tumour grading in the clinic for several decades[5,6], the mechanisms underlying aberrant nuclear morphology in cancer and their impact on genomic integrity remain largely unaddressed[6,7]. De-phosphorylation of myosin light chain is mediated by a protein phosphatase 1 (PP1) complex containing the regulatory subunit, PPP1R12A ( known as MYPT1)[14]. Our data suggest that nuclear dysmorphia of cancer cells and nuclear shape in general is controlled by the opposing activities of actomyosin contractility promoting factors and myosin phosphatase

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Conclusion