Nuclear Deformation Causes DNA Damage by Increasing Replication Stress.

摘要: Cancer metastasis, i.e., the spreading of tumor cells from primary to distant organs, is responsible for vast majority cancer deaths. In process, migrate through narrow interstitial spaces substantially smaller in cross-section than cell. During such confined migration, experience extensive nuclear deformation, envelope rupture, and DNA damage. The molecular mechanisms migration-induced damage remain incompletely understood. Although some cell lines, closely associated with we show that, others, mechanical deformation nucleus sufficient cause damage, even absence rupture. This deformation-induced unlike nuclear-envelope-rupture-induced occurs primarily S/G2 phase cycle replication forks. Nuclear resulting either migration or external compression, increases stress, possibly by increasing fork stalling, providing a mechanism Thus, have uncovered new mechanically induced linking stress. could not only increase genomic instability metastasizing but also non-migrating tissues that compression during development, thereby contributing tumorigenesis response activation.