10th Annual Symposium
Physics of Cancer
Leipzig, Germany
September 25-27, 2019
Invited Talk
Nuclear Rupture at high curvature and high rates leads to defects in DNA repair to affect cell cycle, differentiation, and genome variation
Dennis Discher
Molecular & Cell Biophysics Lab, Univ. Pennsylvania, Philadelphia, PA, USA
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The nucleus links physically to cytoskeleton, adhesions, and extracellular matrix – all of which are subject to forces. We find nuclear rupture in tumors [1], embryonic organs [2], and various in vitro models results from high nuclear curvature and leads to cytoplasmic mis-localization of multiple DNA repair factors and transcription factors. Curvature is imposed by an external probe [1], by migrating quickly (not slowly) through small constricting pores [3,4], or simply by cell attachment to either aligned collagen fibers or stiff matrix [1], and theory indicates heterogeneous nucleation for pore formation [5]. Mis-localization of nuclear factors is greatly enhanced by depleting lamin A, requires many hours for nuclear re-entry, and correlates with pan-nucleoplasmic foci of the DNA damage marker γH2AX and with electrophoretic breaks. Excess DNA damage is rescued in ruptured nuclei by co-overexpression of multiple DNA repair factors as well as by soft matrix or inhibition of actomyosin tension and oxidative processes – with combination treatments needed to rescue cell cycle suppression [4]. Increased contractility has the opposite effect, and stiff tumors with low lamin A indeed exhibit increased nuclear curvature, more frequent nuclear rupture, and excess DNA damage. Normal differentiation processes of myogenesis and ostoegenesis are also affected, but oppositely by migration through constricting pores, suggesting general effects on cell fates [6]. Mis-repair of DNA is further suggested by two cancer lines that, after constricted migration, exhibit greater genome variation [1,3].
[1]Y Xia, D Discher. Nuclear rupture at sites of high curvature compromises retention of DNA repair factors, J Cell Biol (2018)
[2]S Cho, D DischerMechanosensing by the lamina protects against nuclear rupture, DNA damage, and cell cycle arrest, Dev Cell (2019)
[3]J Irianto, D DischerDNA damage follows repair factor depletion and portends genome variation in cancer cells after pore migration, Curr Biol (2017)
[4]Y Xia, D DischerRescue of DNA damage after constricted migration reveals bimodal mechano-regulation of cell cycle, J Cell Biol (2019)
[5]D Deviri, D Discher DE, SA SafranScaling laws indicate distinct nucleation mechanisms of holes in the nuclear lamina, Nature Physics (2019)
[6]LR SmithConstricted migration modulates stem cell differentiation, Mol Biol of the Cell (2019)
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