Function of chromatin structure and dynamics in DNA damage, repair and misrepair: γ-rays and protons in action

Ježková, Lucie; Falk, Martin; Falková, Iva; Davídková, Marie; Bačı́ková, Alena; Štefančíková, Lenka; Vachelová, Jana; Michaelidesová, Anna; Lukášová, Emı́lie; Boreyko, A. V.; Krasavin, E. A.; Kozubek, Stanislav

doi:10.1016/j.apradiso.2013.01.022

Cited by 24 publications

(26 citation statements)

References 37 publications

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“…RIF are not readily detected in the centre of hetero chromatic regions follow ing ionizing radiation, but damaged DNA seems to relocate to the periphery of these regions where ATM-dependent repair occurs, [53][54][55] which slows the repair process compared with DNA damage that occurs in euchromatin. [56][57][58] These differences have been found with the use of both sparse and dense ionizing radiation, and have led to the conclusion that chromatin and nuclear architecture influences the dynamics and extent of DNA damage and repair even within one cell-cycle phase. Extrapolating these data to cell survival needs caution, but several reports suggest that radioresistant cells have higher heterochromatin levels than radiosensitive cells.…”

Section: Chromatin Structure and Targetingmentioning

confidence: 95%

Opportunities and challenges of radiotherapy for treating cancer

2015

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The past 20 years have seen dramatic changes in the delivery of radiation therapy, but the impact of radiobiology on the clinic has been far less substantial. A major consideration in the use of radiotherapy has been on how best to exploit differences between the tumour and host tissue characteristics, which in the past has been achieved empirically by radiation-dose fractionation. New advances are uncovering some of the mechanistic processes that underlie this success story. In this Review, we focus on how these processes might be targeted to improve the outcome of radiotherapy at the individual patient level. This approach would seem a more productive avenue of treatment than simply trying to increase the radiation dose delivered to the tumour.

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Section: Chromatin Structure and Targetingmentioning

confidence: 95%

Opportunities and challenges of radiotherapy for treating cancer

2015

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“…high-LET and low-LET) might differently interact with structurally and functionally distinct higher order chromatin domains (discussed in [ 1] and citations therein); this might be reflected by DNA double strand break (DSB) repair efficiency and the mechanism of how cancerogenous chromosomal translocations (CHT) form. Therefore, we compared the DSB repair kinetics and formation of γH2AX/p53BP1 repair clusters upon the action of γ-rays [ 2, 3], protons (15 and 30 MeV) [ 4], and 20 Ne ions (preliminary data). Consequently, we discuss biological impacts of these clusters.…”

mentioning

confidence: 99%

“…Therefore, we compared the DSB repair kinetics and formation of γH2AX/p53BP1 repair clusters upon the action of γ-rays [ 2, 3], protons (15 and 30 MeV) [ 4], and 20 Ne ions (preliminary data). Consequently, we discuss biological impacts of these clusters. Material and methods: Immunostaining methods in combination with high-resolution confocal microscopy, performed on 3D-fixed normal human skin fibroblasts [ 2– 4], were used to study initial distributions of γH2AX and p53BP1 repair foci and their changes during the post-irradiation (PI) time, with a special concern on foci clustering. Irradiations with γ-rays, protons of different energies (15 and 30 MeV), and high-LET 20 Ne ions was performed in IBP ASCR Brno (CR), NPI AVCR Řež (CR) and JINR Dubna (Russia), respectively.…”

mentioning

confidence: 99%

“…Secondary clusters of primary clusters (higher-order clusters) observed for 20 Ne ions might explain frequent formation of complex translocations upon the action of high-LET radiations. Finally, we suggest [ 1, 2, 4] a model that describes the relationship between the higher order chromatin structure, DSB formation, repair and misrepair.…”

mentioning

confidence: 99%

“…Material and methods: Immunostaining methods in combination with high-resolution confocal microscopy, performed on 3D-fixed normal human skin fibroblasts [ 2– 4], were used to study initial distributions of γH2AX and p53BP1 repair foci and their changes during the post-irradiation (PI) time, with a special concern on foci clustering. Irradiations with γ-rays, protons of different energies (15 and 30 MeV), and high-LET 20 Ne ions was performed in IBP ASCR Brno (CR), NPI AVCR Řež (CR) and JINR Dubna (Russia), respectively.…”

mentioning

confidence: 99%

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Primary and secondary clustering of DSB repair foci and repair kinetics compared for -rays, protons of different energies and high-LET 20Ne ions

Falk

Lukášová

Falková

et al. 2014

Journal of Radiation Research

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Purpose: Ionizing radiations of different qualities (e.g. high-LET and low-LET) might differently interact with structurally and functionally distinct higher order chromatin domains (discussed in [ 1] and citations therein); this might be reflected by DNA double strand break (DSB) repair efficiency and the mechanism of how cancerogenous chromosomal translocations (CHT) form. Therefore, we compared the DSB repair kinetics and formation of γH2AX/p53BP1 repair clusters upon the action of γ-rays [ 2, 3], protons (15 and 30 MeV) [ 4], and 20Ne ions (preliminary data). Consequently, we discuss biological impacts of these clusters.Material and methods: Immunostaining methods in combination with high-resolution confocal microscopy, performed on 3D-fixed normal human skin fibroblasts [ 2– 4], were used to study initial distributions of γH2AX and p53BP1 repair foci and their changes during the post-irradiation (PI) time, with a special concern on foci clustering. Irradiations with γ-rays, protons of different energies (15 and 30 MeV), and high-LET 20Ne ions was performed in IBP ASCR Brno (CR), NPI AVCR Řež (CR) and JINR Dubna (Russia), respectively.Results: Upon irradiating cells with 20Ne ions, tracks of multiple clustered γH2AX and p53BP1 repair foci appeared immediately after the irradiation; these clusters, called here as the ‘primary clusters’, were rare in cells irradiated with γ-rays or protons (submitted). Though γH2AX/p53BP1 foci were positionally quite stable [ 2], ‘secondary clusters’ occasionally appeared after all kinds of irradiation during about 30 min PI. The formation of secondary clusters usually appeared due to the heterochromatin decondensation at the sites of heterochromatic DNA double-strand breaks (hcDSBs), followed by their protrusion into a limited space of nuclear subdomains of low density-chromatin (discussed in [ 1, 2, 5]).Conclusions: Primary clusters appear in cell nuclei immediately PI as the consequence of highly localized energy deposition, while secondary clusters develop during (and because of) DSB repair. Primary DSB clusters probably represent the main cause of chromosomal translocations induced with high-LET radiations while secondary clusters seem to be more important for low-LET γ-rays and protons. Secondary clusters of primary clusters (higher-order clusters) observed for 20Ne ions might explain frequent formation of complex translocations upon the action of high-LET radiations. Finally, we suggest [ 1, 2, 4] a model that describes the relationship between the higher order chromatin structure, DSB formation, repair and misrepair.

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