Matrix Rigidity Myosin-Ii And Lamin-A Regulate Curvature Induced Nuclear Rupture Causing Repair Factor Mislocalization And Dna Damage

Mechanosensing of matrix stiffness can increase the activity and/or expression of major structural proteins, including myosin-II and lamin-A, both of which are sometimes dysregulated in cancer. Genome instability is a hallmark of cancer, and here we show that nuclear rupture of cancer cells with low lamin-A or high myosin-II increases with matrix stiffness, which causes multiple DNA repair factors to mis-localize to the cytoplasm and DNA damage to increase. Soft matrix and inhibition of cytoskeletal stress relax nuclear curvature, suppress rupture, and minimize the pan-nucleoplasmic pattern of DNA damage. Partial knockdown of multiple repair factors causes similar DNA damage without rupture. 3D-migration of wildtype cancer cells through highly curved rigid pores also causes myosin-dependent nuclear rupture and DNA damage which is rescued by co-overexpression of multiple repair factors. A cytoplasmic nuclease has no effect when overexpressed. Tumors with low lamin-A likewise exhibit elevated nuclear rupture and DNA damage, consistent with tumor rigidity effects and the effects of nuclear stress in vivo.