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Actin-myosin–based contraction is responsible for apoptotic nuclear disintegration

¹ Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, PA 19104
² The Breakthrough Tony Robins Breast Cancer Research Centre, Institute of Cancer Research, London SW3 6JB, England, UK
³ Cancer and Developmental Biology Laboratory, Center for Cancer Research, National Cancer Institute at Frederick, Frederick, MD 21702

Correspondence to Michael Olson: m.olson{at}beatson.gla.ac.uk

Membrane blebbing during the apoptotic execution phase results from caspase-mediated cleavage and activation of ROCK I. Here, we show that ROCK activity, myosin light chain (MLC) phosphorylation, MLC ATPase activity, and an intact actin cytoskeleton, but not microtubular cytoskeleton, are required for disruption of nuclear integrity during apoptosis. Inhibition of ROCK or MLC ATPase activity, which protect apoptotic nuclear integrity, does not affect caspase-mediated degradation of nuclear proteins such as lamins A, B1, or C. The conditional activation of ROCK I was sufficient to tear apart nuclei in lamin A/C null fibroblasts, but not in wild-type fibroblasts. Thus, apoptotic nuclear disintegration requires actin-myosin contractile force and lamin proteolysis, making apoptosis analogous to, but distinct from, mitosis where nuclear disintegration results from microtubule-based forces and from lamin phosphorylation and depolymerization.

Abbreviations used in this paper: 4-HT, 4-hydroxytamoxifen; CHX, cycloheximide; LAP, lamin-associated protein; LIMK, LIM kinase; MEF, mouse embryo fibroblast; MLC, myosin light chain; PARP, poly-ADP ribose polymerase; TEM, transmission EM.

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