Subdiffusion Supports Joining Of Correct Ends During Repair Of DNA Double-Strand Breaks

Girst, Stefanie; Hable, V.; Drexler, G.; Greubel, C.; Siebenwirth, Christian; Haum, M.; Friedl, Anna A.; Dollinger, G.

doi:10.1038/srep02511

Cited by 38 publications

(43 citation statements)

References 37 publications

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“…Focused particle microbeams are a potentially effective way to probe the interaction of the DSB formed along different particle tracks. For example, Girst et al . used live‐cell observations and distance tracking of the GFP‐tagged DNA damage response protein MDC1 to study the random‐walk behavior of DSB formed in chromatin domains by 20 MeV proton and 43 MeV carbon ions.…”

Section: Model Testing and Clinical Validation Of Rbe Modelsmentioning

confidence: 99%

“…Focused particle microbeams [152][153][154][155][156][157][158][159] are a potentially effective way to probe the interaction of the DSB formed along different particle tracks. For example, Girst et al 160 used live-cell observations and distance tracking of the GFP-tagged DNA damage response protein MDC1 to study the random-walk behavior of DSB formed in chromatin domains by 20 MeV proton and 43 MeV carbon ions. They found that the subrandom-walk confinement of DSB to domains smaller than the diameter of the cell nucleus increases correct break-end rejoining and decreases the chance of long-range movements and, therefore, also decreases the chance pairwise DSB interactions create lethal chromosome aberrations.…”

Section: Model Testing and Clinical Validation Of Rbe Modelsmentioning

confidence: 99%

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A comparison of mechanism‐inspired models for particle relative biological effectiveness (RBE)

et al. 2018

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Background and Significance The application of heavy ion beams in cancer therapy must account for the increasing relative biological effectiveness (RBE) with increasing penetration depth when determining dose prescriptions and organ at risk (OAR) constraints in treatment planning. Because RBE depends in a complex manner on factors such as the ion type, energy, cell and tissue radiosensitivity, physical dose, biological endpoint, and position within and outside treatment fields, biophysical models reflecting these dependencies are required for the personalization and optimization of treatment plans. Aim To review and compare three mechanism‐inspired models which predict the complexities of particle RBE for various ion types, energies, linear energy transfer (LET) values and tissue radiation sensitivities. Methods The review of models and mechanisms focuses on the Local Effect Model (LEM), the Microdosimetric‐Kinetic (MK) model, and the Repair‐Misrepair‐Fixation (RMF) model in combination with the Monte Carlo Damage Simulation (MCDS). These models relate the induction of potentially lethal double strand breaks (DSBs) to the subsequent interactions and biological processing of DSB into more lethal forms of damage. A key element to explain the increased biological effectiveness of high LET ions compared to MV x rays is the characterization of the number and local complexity (clustering) of the initial DSB produced within a cell. For high LET ions, the spatial density of DSB induction along an ion's trajectory is much greater than along the path of a low LET electron, such as the secondary electrons produced by the megavoltage (MV) x rays used in conventional radiation therapy. The main aspects of the three models are introduced and the conceptual similarities and differences are critiqued and highlighted. Model predictions are compared in terms of the RBE for DSB induction and for reproductive cell survival. Results and Conclusions Comparisons of the RBE for DSB induction and for cell survival are presented for proton (1H), helium (4He), and carbon (12C) ions for the therapeutically most relevant range of ion beam energies. The reviewed models embody mechanisms of action acting over the spatial scales underlying the biological processing of potentially lethal DSB into more lethal forms of damage. Differences among the number and types of input parameters, relevant biological targets, and the computational approaches among the LEM, MK and RMF models are summarized and critiqued. Potential experiments to test some of the seemingly contradictory aspects of the models are discussed.

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Section: Model Testing and Clinical Validation Of Rbe Modelsmentioning

confidence: 99%

Section: Model Testing and Clinical Validation Of Rbe Modelsmentioning

confidence: 99%

A comparison of mechanism‐inspired models for particle relative biological effectiveness (RBE)

et al. 2018

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“…A DSB causes local changes in the mobility of chromatin; modeling predicts an increased mobility due to entropic effects [78], but motion in vivo is subdiffusional [79] which reduces the probability of long-range movements. The broken ends adopt more peripheral positions in chromosomes [78], favoring their meeting and rejoining.…”

Section: Finding Targets In the Genomementioning

confidence: 99%

Structures and functions in the crowded nucleus: new biophysical insights

Hancock

2014

Front. Phys.

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Concepts and methods from the physical sciences have catalyzed remarkable progress in understanding the cell nucleus in recent years. To share this excitement with physicists and encourage their interest in this field, this review offers an overview of how the physics which underlies structures and functions in the nucleus is becoming more clear thanks to methods which have been developed to simulate and study macromolecules, polymers, and colloids. The environment in the nucleus is very crowded with macromolecules, making entropic (depletion) forces major determinants of interactions. Simulation and experiments are consistent with their key role in forming membraneless compartments such as nucleoli, PML and Cajal bodies, and discrete "territories" for chromosomes. The chromosomes, giant linear polyelectrolyte polymers, exist in vivo in a state like a polymer melt. Looped conformations are predicted in crowded conditions, and have been confirmed experimentally and are central to the regulation of gene expression. Polymer theory has revealed how the chromosomes are so highly compacted in the nucleus, forming a "crumpled globule" with fractal properties which avoids knots and entanglements in DNA while allowing facile accessibility for its replication and transcription. Entropic repulsion between looped polymers can explain the confinement of each chromosome to a discrete region of the nucleus. Crowding and looping are predicted to facilitate finding the specific targets of factors which modulate activities of DNA. Simulation shows that entropic effects contribute to finding and repairing potentially lethal double-strand breaks in DNA by increasing the mobility of the broken ends, favoring their juxtaposition for repair. Signaling pathways are strongly influenced by crowding, which favors a processive mode of response (consecutive reactions without releasing substrates). This new information contributes to understanding the sometimes counter-intuitive consequences and the evolutionary advantages of a crowded environment in the nucleus.

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“…It has been experimentally demonstrated that double strand breaks move by sub-diffusion (Girst et al, 2013;Lucas et al, 2014;Miné-Hattab et al, 2017), and, although not explicitly concluded, there is experimental evidence that this applies to individual double strand break ends (Soutoglou et al, 2007). To the best of our knowledge this type of motion has not yet been explicitly included in any mechanistic in silico models of DNA repair.…”

Section: Motionmentioning

confidence: 99%

AnIn SilicoModel of DNA Repair for Investigation of Mechanisms in Non-Homologous End Joining

Warmenhoven¹,

Henthorn²,

Sotiropoulos³

et al. 2018

Preprint

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In human cells, non-homologous end joining is the preferred process to repair radiation induced DNA double strand breaks. The complex nature of such biological systems involves many individual actions that combine to produce an overall behaviour. As such, experimentally determining the mechanisms involved, their individual roles, and how they interact is challenging. An in silico approach to radiobiology is uniquely suited for detailed exploration of these complex interactions and the unknown effects of specific mechanisms on overall behaviour. We detail the construction of a mechanistic model by combination of several, experimentally supported, hypothesised mechanisms.Compatibility of these mechanisms was tested by fitting to results reported in the literature. To avoid over fitting, individual mechanisms within this pathway were sequentially fitted. We demonstrate that using this approach the model is capable of reproducing published protein kinetics and overall repair trends. This process highlighted specific biological mechanisms which are not clearly defined experimentally, and showed that the assumed motion of individual double strand break ends plays a crucial role in determining overall system behaviour.

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Subdiffusion Supports Joining Of Correct Ends During Repair Of DNA Double-Strand Breaks

Cited by 38 publications

References 37 publications

A comparison of mechanism‐inspired models for particle relative biological effectiveness (RBE)

A comparison of mechanism‐inspired models for particle relative biological effectiveness (RBE)

Structures and functions in the crowded nucleus: new biophysical insights

AnIn SilicoModel of DNA Repair for Investigation of Mechanisms in Non-Homologous End Joining

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