Activation of the DNA-repair mechanism through NBS1 and MRE11 diffusion

The non-homologous end joining of a DNA double strand break is initiated by the MRE11-NBS1-RAD50 complex whose subunits are the first three proteins to arrive to the breakage site thereby making the recruitment time of MRE11, NBS1 and RAD50 essential for cell survival. In the present investigation, the nature of MRE11 and NBS1 transportation from the cytoplasm to the nucleus, hosting the damaged DNA strand, is hypothesized to be a passive diffusive process. The feasibility of such a mechanism is addressed through theoretical and computational approaches which permit establishing the characteristic recruitment time of MRE11 and NBS1 by the nucleus. A computational model of a cell is constructed from a set of biological parameters and the kinetic Monte Carlo algorithm is used to simulate the diffusing MRE11 and NBS1 particles as a random walk process. To accurately describe the experimented data, it is discovered that MRE11 and NBS1 should start diffusion from significantly different starting positions which suggests that diffusion might not be the only transport mechanism of repair protein recruitment to the DNA break.Author summary: The DNA repair mechanism is crucial for a cell to avoid apoptosis, and is a complicated process involving many different repair proteins. The mean of transportation of these repair proteins is largely unknown as their transportation mechanisms need clarification. We have focused on the transportation of some of the first proteins to arrive to the damaged DNA from the cytoplasm, namely the MRE11 and NBS1. Our hypothesis of diffusion as the transportation mechanism of MRE11 and NBS1 is tested against a theoretical model as well as simulation data and experiments, revealing a possibility for diffusion to be the method of recruiting MRE11 and NBS1 to the DNA break.