A quantitative model of the major pathways for radiation-induced DNA double-strand break repair

Belov, Oleg; Krasavin, E. A.; Lyashko, Marina S.; Batmunkh, Munkhbaatar; Sweilam, N. H.

doi:10.1016/j.jtbi.2014.09.024

“…In the case of high LET radiation, more than 90% lesions are associated with very complex damages. Several repair pathways, including NHEJ, homologous recombination, microhomology-mediated end-joining, and alternative nonhomologous end-joining, may sequentially attempt to recover it 55 . The choice of the appropriate pathway is regulated by three major factors, which include the damage complexity, cell cycle phase, and the speed of different repair mechanisms 56 .…”

Section: Resultsmentioning

confidence: 99%

A generalized target theory and its applications

Zhao

¹

,

Mi

²

,

Hu

³

et al. 2015

Sci Rep

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Different radiobiological models have been proposed to estimate the cell-killing effects, which are very important in radiotherapy and radiation risk assessment. However, most applied models have their own scopes of application. In this work, by generalizing the relationship between “hit” and “survival” in traditional target theory with Yager negation operator in Fuzzy mathematics, we propose a generalized target model of radiation-induced cell inactivation that takes into account both cellular repair effects and indirect effects of radiation. The simulation results of the model and the rethinking of “the number of targets in a cell” and “the number of hits per target” suggest that it is only necessary to investigate the generalized single-hit single-target (GSHST) in the present theoretical frame. Analysis shows that the GSHST model can be reduced to the linear quadratic model and multitarget model in the low-dose and high-dose regions, respectively. The fitting results show that the GSHST model agrees well with the usual experimental observations. In addition, the present model can be used to effectively predict cellular repair capacity, radiosensitivity, target size, especially the biologically effective dose for the treatment planning in clinical applications.

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“…Despite our demonstra-tion that the model is predictive across multiple doses in the low LET regime, we modelled repair following a variety of radiation doses, and we can't rule out that complexity of DSBs further alters the dynamics of repair. Previous studies have also modelled the formation of foci by summing the DSB enzymes involved in the phosphorylation of H2AX [48,52] and using this approach, our model could be developed to take into account lower doses of radiation or the dynamics of γ-H2AX foci formation. Related complicating factors are clustered DSBs [79] and DSBs residing in heterochromatic regions, which have been shown to require Artemis for repair [80].…”

Section: Discussionmentioning

confidence: 99%

“…This could be because γ-H2AX is involved in the recruitment of repair complexes and because H2AX is present in clusters in bulk chromatin, the spreading of γ-H2AX is assumed to be non uniform [80]. Previous studies have modelled the formation of foci by summing the DSB enzymes involved in the phosphorylation of H2AX [53,57] and using this approach, our model could be developed to take into account lower doses of radiation.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Mechanistic modelling and Bayesian inference elucidates the variable dynamics of double-strand break repair

Barnes

¹

,

Woods

²

2015

Preprint

0

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DNA double-strand breaks are lesions that form during metabolism, DNA replication and exposure to mutagens. When a double-strand break occurs one of a number of repair mechanisms is recruited, all of which have differing propensities for mutational events. Despite DNA repair being of crucial importance, the relative contribution of these mechanisms and their regulatory interactions remain to be fully elucidated. Understanding these mutational processes will have a profound impact on our knowledge of genomic instability, with implications across health, disease and evolution. Here we present a new method to model the combined activation of non-homologous end joining, single strand annealing and alternative end joining, following exposure to ionising radiation. We use Bayesian statistics to integrate eight biological data sets of double-strand break repair curves under varying genetic knockouts and confirm that our model is predictive by re-simulating and comparing to additional data. Analysis of the model suggests that there are at least three disjoint modes of repair, which we assign as fast, slow and intermediate. Our results show that when multiple data sets are combined, the rate for intermediate repair is variable amongst genetic knockouts. Further analysis suggests that the ratio between slow and intermediate repair depends on the presence or absence of DNA-PKcs and Ku70, which implies that non-homologous end joining and alternative end joining are not independent. Finally, we consider the proportion of double-strand breaks within each mechanism as a time series and predict activity as a function of repair rate. We outline how our insights can be directly tested using imaging and sequencing techniques and conclude that there is evidence of variable dynamics in alternative repair pathways. Our approach is an important step towards providing a unifying theoretical framework for the dynamics of DNA repair processes. Author SummaryDNA double-strand breaks occur during metabolism, DNA replication and by exposure to exogenous sources such as ionising radiation. When the genome is inflicted with this type of damage, DNA repair machinery is promoted to restore genome structure. The efficient interplay between DNA damage and repair is crucial to genome stability because the choice of repair mechanism directly affects the probability of mutation. Multiple mechanisms of DNA repair are known to exist, however, the subtleties of how they are activated and their interactions are yet to be fully determined. We hypothesise that a combination of Bayesian statistics and mathematical modeling is essential to elucidate the network dynamics. Studies in the literature have presented time series data of double-strand break repair in wild type and mutant cells. By combining existing time series data, our modeling approach can quantify the differences in activation amongst mutants and in addition identify a number of novel insights into the dynamics of the competing mechanisms. We conclude that alternative mechanisms of rep...

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“…Mathematical models of DSB repair have used biphasic [ 46 ], biochemical kinetic [ 47 – 52 ], multi-scale [ 53 , 54 ], and stochastic methods [ 55 ]. In a study by Cucinotta et al .…”

Section: Introductionmentioning

confidence: 99%

Mechanistic Modelling and Bayesian Inference Elucidates the Variable Dynamics of Double-Strand Break Repair

Woods

¹

,

Barnes

²

2016

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DNA double-strand breaks are lesions that form during metabolism, DNA replication and exposure to mutagens. When a double-strand break occurs one of a number of repair mechanisms is recruited, all of which have differing propensities for mutational events. Despite DNA repair being of crucial importance, the relative contribution of these mechanisms and their regulatory interactions remain to be fully elucidated. Understanding these mutational processes will have a profound impact on our knowledge of genomic instability, with implications across health, disease and evolution. Here we present a new method to model the combined activation of non-homologous end joining, single strand annealing and alternative end joining, following exposure to ionising radiation. We use Bayesian statistics to integrate eight biological data sets of double-strand break repair curves under varying genetic knockouts and confirm that our model is predictive by re-simulating and comparing to additional data. Analysis of the model suggests that there are at least three disjoint modes of repair, which we assign as fast, slow and intermediate. Our results show that when multiple data sets are combined, the rate for intermediate repair is variable amongst genetic knockouts. Further analysis suggests that the ratio between slow and intermediate repair depends on the presence or absence of DNA-PKcs and Ku70, which implies that non-homologous end joining and alternative end joining are not independent. Finally, we consider the proportion of double-strand breaks within each mechanism as a time series and predict activity as a function of repair rate. We outline how our insights can be directly tested using imaging and sequencing techniques and conclude that there is evidence of variable dynamics in alternative repair pathways. Our approach is an important step towards providing a unifying theoretical framework for the dynamics of DNA repair processes.

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A quantitative model of the major pathways for radiation-induced DNA double-strand break repair

Cited by 35 publications

References 86 publications

A generalized target theory and its applications

A generalized target theory and its applications

Mechanistic modelling and Bayesian inference elucidates the variable dynamics of double-strand break repair

Mechanistic Modelling and Bayesian Inference Elucidates the Variable Dynamics of Double-Strand Break Repair

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