RT Journal Article
SR Electronic
T1 Nuclear deformation causes DNA damage by increasing replication stress
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2020.06.12.148890
DO 10.1101/2020.06.12.148890
A1 Shah, Pragya
A1 Hobson, Chad M.
A1 Cheng, Svea
A1 Colville, Marshall
A1 Paszek, Matthew
A1 Superfine, Richard
A1 Lammerding, Jan
YR 2020
UL http://biorxiv.org/content/early/2020/10/21/2020.06.12.148890.abstract
AB Cancer metastasis, i.e., the spreading of tumor cells from the primary tumor to distant organs, is responsible for the vast majority of cancer deaths. In the process, cancer cells migrate through narrow interstitial spaces substantially smaller in cross-section than the cell. During such confined migration, cancer cells experience extensive nuclear deformation, nuclear envelope rupture, and DNA damage. The molecular mechanisms responsible for the confined migration-induced DNA damage remain incompletely understood. While in some cell lines, DNA damage is closely associated with nuclear envelope rupture, we show that in others, mechanical deformation of the nucleus is sufficient to cause DNA damage, even in the absence of nuclear envelope rupture. This deformation-induced DNA damage, unlike nuclear envelope rupture-induced DNA damage, occurs primarily in S/G2 phase of the cell cycle and is associated with replication forks. Nuclear deformation, resulting from either confined migration or external cell compression, increases replication stress, possibly by increasing replication fork stalling, providing a molecular mechanism for the deformation-induced DNA damage. Thus, we have uncovered a new mechanism for mechanically induced DNA damage, linking mechanical deformation of the nucleus to DNA replication stress. This mechanically induced DNA damage could not only increase genomic instability in metastasizing cancer cells, but could also cause DNA damage in non-migrating cells and tissues that experience mechanical compression during development, thereby contributing to tumorigenesis and DNA damage response activation.Competing Interest StatementThe authors have declared no competing interest.