Cyclic stretch-induced mechanical stress to the cell nucleus inhibits ultraviolet radiation-induced DNA damage.

Abstract

Ultraviolet (UV) radiation exerts adverse effects on genome stability, alters the normal state of life, and causes several diseases by inducing DNA damage. Although mechanical stimulation such as stretching has significant effects on the prevention and treatment of diseases, its influence on nuclear morphology and/or intranuclear functions involving resistance to DNA damage remains unknown. Here, we investigated the effects of mechanical stimulation by cyclic stretching on nuclear morphology and resistance of DNA to UV damage in NIH3T3 fibroblasts. Adherent cells on silicone elastic membranes were subjected to ~ 10% cyclic uniaxial stretch at a frequency of 0.5Hz for 12h. As a result, the intracellular actin cytoskeleton and nucleus were found to be elongated and aligned in the direction of zero normal strain (~ 62° with respect to the stretch direction) in an actomyosin tension-dependent manner. The nuclei of the stretched cells were dramatically compressed by the reorganized actin stress fibers located on their apical and both sides, and a significant increase in the intranuclear DNA density was observed. Intercellular tension, as assessed with live cell atomic force microscopy imaging, also increased following exposure to cyclic stretch. The UV radiation-induced DNA damage, estimated from the fluorescence intensity of the phospho-histone γ-H2AX, significantly decreased in these stretched cells. These results indicate that the cyclic stretch-induced morphological changes in the nucleus may improve the UV radiation resistance of cells, probably owing to the intracellular force-induced condensation of chromatin. To our knowledge, this is the first study to demonstrate the inhibition of the UV radiation-induced DNA damage by mechanical stimulation.