Nuclear dynamics of radiation-induced foci in euchromatin and heterochromatin

Chiolo, Irene; Tang, Jonathan; Georgescu, Walter; Costes, Sylvain V.

doi:10.1016/j.mrfmmm.2013.08.001

Cited by 69 publications

(114 citation statements)

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“…Evidence suggesting that RIF move over large distances in the nucleus has recently been reviewed [14]. From this body of work, we hypothesize that DSBs can merge into repair domains [13].…”

Section: Modeling and Validating Dsb Clustering Modelmentioning

confidence: 85%

“…As previously suggested [30 31], such a mechanism would be an efficient and physiological way to deal with lesions in the very low dose range (mGy) as the majority of the lesions would remain isolated into one repair domain. On the other hand, at higher doses or along high-LET tracks, DSBs clustering could increase risk of translocations and cell death, as recently reviewed [14]. For example, DSB clustering in human white blood cells has been proposed as a mechanism for chromosomal rearrangements observed after exposure to densely ionizing radiation [32].…”

Section: Discussionmentioning

confidence: 99%

“…We recently reported that clustered RIF are more persistent than isolated RIF [14], suggesting that DSBs associated with RIF clusters are more difficult to repair. In agreement, the LEM model assumes that DSBs in close proximity have a higher probability of inducing cell death than isolated DSBs [36 37].…”

Section: Discussionmentioning

confidence: 99%

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Combinatorial DNA Damage Pairing Model Based on X-Ray-Induced Foci Predicts the Dose and LET Dependence of Cell Death in Human Breast Cells

et al. 2014

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In contrast to the classic view of static DNA double strand breaks (DSBs) being repaired at the site of damage, we hypothesize that DSBs move and merge with each other over large distances (µm). As X-ray dose increases, the probability of having DSB clusters increases and so does the probability of misrepair and cell death. Experimental work characterizing the dose dependence of radiation-induced foci (RIF) from X-ray in nonmalignant human mammary epithelial cells (MCF10A) is used here to validate a DSB clustering model. We then use the principles of the local effect model (LEM) to predict the yield of DSB at the sub-micron level. Two mechanisms for DSB clustering are first compared: random coalescence of DSBs versus active movement of DSBs into repair domains. Simulations that best predict both RIF dose dependence and cell survival following X-ray favor the repair domain hypothesis, suggesting the nucleus is divided into an array of regularly spaced repair domains of ~1.55 µm sides. Applying the same approach to high-LET ion tracks, we can predict experimental RIF/µm along tracks with an overall relative error of 12%, for LET ranging between 30 and 350 keV/µm and for three different ions. Finally, cell death is predicted by assuming an exponential dependence on the total number of DSBs and of all possible combinations of paired DSBs within each simulated RIF. RBE predictions for cell survival of MCF10A exposed to high-LET show an LET dependence that matches previous experimental results for similar cell types. Overall, this work suggests that microdosimetric properties of ion tracks at the sub-micron level are sufficient to explain both RIF data and survival curves for any LET, similarly to the LEM assumption. On the other hand, high-LET death mechanism does not have to infer linear-quadratic dose formalism as done in the LEM. In addition, the size of repair domains derived in our model are based on experimental RIF and are three times larger than the hypothetical LEM voxel used to fit survival curves. Our model is therefore an alternative to previous approaches by providing a testable biological mechanism (i.e. RIF). More generally, DSB pairing will help develop more accurate alternatives to the simplistic linear cancer risk model (LNT) currently used for regulating exposure to very low levels of ionizing radiation.Vadhavkar et al.

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“…Evidence suggesting that RIF move over large distances in the nucleus has recently been reviewed [14]. From this body of work, we hypothesize that DSBs can merge into repair domains [13].…”

Section: Modeling and Validating Dsb Clustering Modelmentioning

confidence: 85%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Combinatorial DNA Damage Pairing Model Based on X-Ray-Induced Foci Predicts the Dose and LET Dependence of Cell Death in Human Breast Cells

et al. 2014

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“…Finally, several lines of evidence suggest that DSB repair is differentially regulated in euchromatin and heterochromatin (reviewed in Chiolo et al 2013) with a preferential repair of heterochromatin DSBs by HR in higher eukaryotes (Shibata et al 2011;Kakarougkas et al 2013b). Notably, DNA DSBs in heterochromatin relocalize to euchromatic regions during repair (Jakob et al 2011), and as a consequence heterochromatic regions often appear to lack radiation-induced g-H2AX foci (Cowell et al 2007;Kim et al 2007;Goodarzi et al 2008;Vasireddy et al 2010;Chiolo et al 2011;Jakob et al 2011;Lafon-Hughes et al 2013).…”

Section: Nuclear Compartmentsmentioning

confidence: 99%

Cell Biology of Mitotic Recombination

Lisby

Rothstein

2015

Cold Spring Harb Perspect Biol

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Homologous recombination provides high-fidelity DNA repair throughout all domains of life. Live cell fluorescence microscopy offers the opportunity to image individual recombination events in real time providing insight into the in vivo biochemistry of the involved proteins and DNA molecules as well as the cellular organization of the process of homologous recombination. Herein we review the cell biological aspects of mitotic homologous recombination with a focus on Saccharomyces cerevisiae and mammalian cells, but will also draw on findings from other experimental systems. Key topics of this review include the stoichiometry and dynamics of recombination complexes in vivo, the choreography of assembly and disassembly of recombination proteins at sites of DNA damage, the mobilization of damaged DNA during homology search, and the functional compartmentalization of the nucleus with respect to capacity of homologous recombination.

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“…Other cellular activities occurring within heterochromatin can expose heterochromatic DNA to attacks initiated by DSB-inducing agents. Nevertheless, due to the highly condensed chromatin structure, it is apparent that heterochromatin is less accessible by DSB-inducing agents and has lower sensitivity to DSB induction by radiation [11,56,57].…”

Section: Induction Of Heterochromatic Dsbsmentioning

confidence: 99%

Buried territories: heterochromatic response to DNA double-strand breaks

Feng¹,

Xiang²,

Kong³

et al. 2016

ABBS

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Cellular response to DNA double-strand breaks (DSBs), the most deleterious type of DNA damage, is highly influenced by higher-order chromatin structure in eukaryotic cells. Compared with euchromatin, the compacted structure of heterochromatin not only protects heterochromatic DNA from damage, but also adds an extra layer of control over the response to DSBs occurring in heterochromatin. One key step in this response is the decondensation of heterochromatin structure. This decondensation process facilitates the DNA damage signaling and promotes proper heterochromatic DSB repair, thus helping to prevent instability of heterochromatic regions of genomes. This review will focus on the functions of the ataxia telangiectasia mutated (ATM) signaling cascade involving ATM, heterochromatin protein 1 (HP1), Krüppel-associated box (KRAB)-associated protein-1 (KAP-1), tat-interacting protein 60 (Tip60), and many other protein factors in DSB-induced decondensation of heterochromatin and subsequent repair of heterochromatic DSBs. As some subsets of DSBs may be repaired in heterochromatin independently of the ATM signaling, a possible repair model is also proposed for ATM-independent repair of these heterochromatic DSBs.

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Nuclear dynamics of radiation-induced foci in euchromatin and heterochromatin

Cited by 69 publications

References 114 publications

Combinatorial DNA Damage Pairing Model Based on X-Ray-Induced Foci Predicts the Dose and LET Dependence of Cell Death in Human Breast Cells

Combinatorial DNA Damage Pairing Model Based on X-Ray-Induced Foci Predicts the Dose and LET Dependence of Cell Death in Human Breast Cells

Cell Biology of Mitotic Recombination

Buried territories: heterochromatic response to DNA double-strand breaks

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