Rescue of DNA Damage After Constricted Migration by DNA Repair Factor Overexpression

Abstract

Migration through constricting pores ruptures the nucleus, causes mis-localization of DNA repair factors among other factors, and increases DNA damage. Here, rescue of both nuclear rupture and DNA damage occurs with myosin-II inhibition, whereas co-overexpression of multiple DNA repair factors rescues the DNA damage but not the nuclear rupture. Inhibition of oxidative stress partially rescues the excess DNA damage, but cell cycle delays persist after constricted migration for all methods of rescue. Overexpressed TREX1, which is a cytoplasmic nuclease, does not add to the DNA damage even though it enters the nuclear bleb at the rupture site as does endogenous cytoplasmic cGAS (cyclic GMP-AMP synthase). Genome variation can increase after constricted migration, consistent with effects of DNA damage and similar in magnitude to in vivo variation. A simple model fits nuclear envelope rupture trends in terms of pore curvature, myosin-II activity, and lamina strength.