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

Ida Friis,Ilia A Solov’Yov,Alexandre V Morozov

doi:10.1371/journal.pcbi.1006362

Ida Friis, Ilia A Solov’Yov + Show 1 more

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https://doi.org/10.1371/journal.pcbi.1006362

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Abstract

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.

Highlights

MethodsCellular modelThe biological environment of the damaged DNA is important to be taken into consideration when studying MRE11 and NBS1 diffusion
Once a DNA strand inside a cell nucleus breaks, the ruptured strands are sought mended by a biological multi-step process [1,2,3,4]
The DNA repair mechanism is crucial for a cell to avoid apoptosis, and is a complicated process involving many different repair proteins

Summary

Methods

Cellular modelThe biological environment of the damaged DNA is important to be taken into consideration when studying MRE11 and NBS1 diffusion. In this study a simple model of a cell used to describe the essential biophysics of the MRE11 and NBS1 diffusion process is considered. The biological system is constructed following the known conditions of NBS1 and MRE11 diffusing in eukaryotic cells, modeled after a human bone marrow cell [32]. Since the cellular membrane is largely impermeable in the suggested model, all of the MRE11 and NBS1 proteins are contained inside the cell, and should they hit the membrane, they will bounce of it again. To construct the simple theoretical model of the cell, consider a spherical topology, where the outer membrane is placed at a distance R, the ribosome at a distance r0 and the inner membrane is placed at a distance ra from the cell center.

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