Abstract
The mobility of damaged chromatin regions in the nucleus may affect the probability of mis-repair. In this work, live-cell observation and distance tracking of GFP-tagged DNA damage response protein MDC1 was used to study the random-walk behaviour of chromatin domains containing radiation-induced DNA double-strand breaks (DSB). Our measurements indicate a subdiffusion-type random walk process with similar time dependence for isolated and clustered DSBs that were induced by 20 MeV proton or 43 MeV carbon ion micro-irradiation. As compared to normal diffusion, subdiffusion enhances the probability that both ends of a DSB meet, thus promoting high efficiency DNA repair. It also limits their probability of long-range movements and thus lowers the probability of mis-rejoining and chromosome aberrations.
Highlights
The mobility of damaged chromatin regions in the nucleus may affect the probability of mis-repair
Experimental data on the mobility of break sites in mammalian chromosomes are inconclusive. They rely on labelling the chromatin region containing the double-strand breaks (DSB) by visualizing specific chromatin modifications known to surround the breaks site, such as c-H2AX, or proteins known to bind chromatin in the vicinity of break sites, such as MDC1
A plot of MSD versus observation time allows determining if the particle observed moves via normal diffusion, in which case the MSD is linearly related to time and a diffusion coefficient D can be determined[15,16]
Summary
The mobility of damaged chromatin regions in the nucleus may affect the probability of mis-repair. As compared to normal diffusion, subdiffusion enhances the probability that both ends of a DSB meet, promoting high efficiency DNA repair. It limits their probability of long-range movements and lowers the probability of mis-rejoining and chromosome aberrations. In live-cell analysis, the behaviour of individual foci over time can be observed and several authors measured trajectories in relation to the origin (single particle tracking[13,14]) In this case, thorough correction for translational and rotational movement of the whole nucleus, as well as its deformation, is paramount, since otherwise the measured mean squared displacements MSD(Dt) 5 ,r 2(Dt). C represents the Gamma function and d is the dimension of the analyzed space
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