When cells migrate through constricting pores, they incur DNA damage and develop genomic variation. Experiments show that this damage is not due to DNA breakage from mechanical stress on chromatin in the deformed nucleus. Here we propose a model for a mechanism by which nuclear deformation can lead to DNA damage. We treat the nucleus as an elastic-fluid system with an elastic component (chromatin) and fluid component that can be squeezed out when the nucleus is deformed. We couple the elastic-fluid model to the kinetics of DNA breakage and repair by assuming that the local volume fraction of the elastic component controls the rate of damage per unit volume due to naturally occurring DNA breaks, whereas the volume fraction of the fluid component controls the rate of repair of DNA breaks per unit volume by repair factors, which are soluble in the fluid. By comparing our results to a number of experiments on controlled migration through pores, we show that squeeze-out of the fluid, and hence of the mobile repair factors, is sufficient to account for the extent of DNA damage and genomic variation observed experimentally. We also use our model for migration through a cylindrical pore to estimate the variation with tissue stiffness of the mutation rate in tumors.
Copyright © 2017. Published by Elsevier Inc.