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Subdiffusion supports joining of correct ends during repair of DNA double-strand breaks.

Girst S, Hable V, Drexler GA, Greubel C, Siebenwirth C, Haum M, Friedl AA, Dollinger G - Sci Rep (2013)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Angewandte Physik und Messtechnik LRT2, Universität der Bundeswehr München, 85577 Neubiberg, Germany. stefanie.girst@unibw.de

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.

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Related in: MedlinePlus

Double-logarithmic plot of the squared standard deviations σ2 (±SEM) of the distance changes Δl(Δt) between neighbouring MDC1 foci (filled squares) and second-next neighbours (open circles) in the nuclei of cells irradiated with carbon ions (657 foci pairs from 58 cells, 30–60 time frames per sample).The data are fitted with the power-law function (equation (2)).
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f2: Double-logarithmic plot of the squared standard deviations σ2 (±SEM) of the distance changes Δl(Δt) between neighbouring MDC1 foci (filled squares) and second-next neighbours (open circles) in the nuclei of cells irradiated with carbon ions (657 foci pairs from 58 cells, 30–60 time frames per sample).The data are fitted with the power-law function (equation (2)).

Mentions: For each cell, we determined the standard deviation σ2(Δl(Δt)) of the changes in foci distances Δli(Δt) between neighbouring MDC1 foci as a measure for the underlying random walk process (see SI). Then the time-ensemble average of the “neighbouring” σ2(Δt) from all analyzed carbon irradiated cells was calculated for each Δt and plotted versus Δt in a double-logarithmic plot (Fig. 2, filled squares). A linear increase of log(σ2) with log(Δt) is evident, which demonstrates a power-law dependence of σ2 on Δt (cf. Supplementary equation (S1)): We obtain α = 0.49 ± 0.05 (SEM) and D0.49 = (3.7 ± 0.5) × 10−4 μm2/s0.49 for the next neighbour foci (l ≈ 5 μm) of the carbon irradiated cells (R2 = 0.97, reduced χ2 = 1.6). The value obtained for α significantly differs from α = 1 demonstrating that the mobility of the IRIFs follows a subdiffusion process20. Our data do not support models based on constrained diffusion21, since we did not see indications for a limit to the radius within which the IRIF can diffuse, in spite of the long time range (up to 104 s) observed. In addition, the best least-square fits of constrained diffusion19 (R2 = 0.91, reduced χ2 = 5.0) or a combination of constrained diffusion and normal diffusion of the confinement region (R2 = 0.95, reduced χ2 = 2.8) did not fit the experimental data (Supplementary Fig. S2).


Subdiffusion supports joining of correct ends during repair of DNA double-strand breaks.

Girst S, Hable V, Drexler GA, Greubel C, Siebenwirth C, Haum M, Friedl AA, Dollinger G - Sci Rep (2013)

Double-logarithmic plot of the squared standard deviations σ2 (±SEM) of the distance changes Δl(Δt) between neighbouring MDC1 foci (filled squares) and second-next neighbours (open circles) in the nuclei of cells irradiated with carbon ions (657 foci pairs from 58 cells, 30–60 time frames per sample).The data are fitted with the power-law function (equation (2)).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3753591&req=5

f2: Double-logarithmic plot of the squared standard deviations σ2 (±SEM) of the distance changes Δl(Δt) between neighbouring MDC1 foci (filled squares) and second-next neighbours (open circles) in the nuclei of cells irradiated with carbon ions (657 foci pairs from 58 cells, 30–60 time frames per sample).The data are fitted with the power-law function (equation (2)).
Mentions: For each cell, we determined the standard deviation σ2(Δl(Δt)) of the changes in foci distances Δli(Δt) between neighbouring MDC1 foci as a measure for the underlying random walk process (see SI). Then the time-ensemble average of the “neighbouring” σ2(Δt) from all analyzed carbon irradiated cells was calculated for each Δt and plotted versus Δt in a double-logarithmic plot (Fig. 2, filled squares). A linear increase of log(σ2) with log(Δt) is evident, which demonstrates a power-law dependence of σ2 on Δt (cf. Supplementary equation (S1)): We obtain α = 0.49 ± 0.05 (SEM) and D0.49 = (3.7 ± 0.5) × 10−4 μm2/s0.49 for the next neighbour foci (l ≈ 5 μm) of the carbon irradiated cells (R2 = 0.97, reduced χ2 = 1.6). The value obtained for α significantly differs from α = 1 demonstrating that the mobility of the IRIFs follows a subdiffusion process20. Our data do not support models based on constrained diffusion21, since we did not see indications for a limit to the radius within which the IRIF can diffuse, in spite of the long time range (up to 104 s) observed. In addition, the best least-square fits of constrained diffusion19 (R2 = 0.91, reduced χ2 = 5.0) or a combination of constrained diffusion and normal diffusion of the confinement region (R2 = 0.95, reduced χ2 = 2.8) did not fit the experimental data (Supplementary Fig. S2).

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Angewandte Physik und Messtechnik LRT2, Universität der Bundeswehr München, 85577 Neubiberg, Germany. stefanie.girst@unibw.de

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.

Show MeSH
Related in: MedlinePlus