Repair of HZE-Particle-Induced DNA Double-Strand Breaks in Normal Human Fibroblasts

Asaithamby, Aroumougame; Uematsu, Naoya; Chatterjee, A.; Story, Michael D.; Burma, Sandeep; Chen, David J.

doi:10.1667/rr1165.1

Cited by 147 publications

(121 citation statements)

References 44 publications

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“…Several studies suggest that residual damage, represented by a subset of DSB that cannot be quickly repaired or rejoined and persist for a longer time, is an indicator of the cell killing probability (1)(2)(3)(4)(5). This is qualitatively consistent with observations after high-LET radiation, where typically the yield of initially induced DSB is similar to that of photon radiation (6), but the fraction of residual damage is increased as compared to low-LET radiation, in line with the higher cell killing efficiency of high-LET radiation (7).…”

Section: Introductionsupporting

confidence: 84%

“…Several hypotheses have been discussed concerning the biological interpretation of these two components, and some of these suggest the presence of DNA damages of different severity, which are processed with different kinetics. This hypothesis is also in line with the slower rejoining observed after exposure to high-LET radiations compared to photons (7,(9)(10)(11).…”

Section: Introductionsupporting

confidence: 79%

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Stochastic Simulation of DNA Double-Strand Break Repair by Non-homologous End Joining Based on Track Structure Calculations

2010

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Section: Introductionsupporting

confidence: 84%

Section: Introductionsupporting

confidence: 79%

Stochastic Simulation of DNA Double-Strand Break Repair by Non-homologous End Joining Based on Track Structure Calculations

2010

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“…At higher doses however (1 and 5Gy), a small dose-dependent number of residual persistent spots were detected. These observations are consistent with other reports on rejoining kinetics (34,35,45). It is plausible that the more persistent foci represent sites, where the repair machinery has difficulty repairing the breaks or where repair proceeds slower (46).…”

Section: Discussionsupporting

confidence: 92%

High content image cytometry in the context of subnuclear organization

et al. 2009

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The organization of proteins in space and time is essential to their function. To accurately quantify subcellular protein characteristics in a population of cells with regard for the stochasticity of events in a natural context, there is a fast-growing need for image-based cytometry. Simultaneously, the massive amount of data that is generated by image-cytometric analyses, calls for tools that enable pattern recognition and automated classification. In this article, we present a general approach for multivariate phenotypic profiling of individual cell nuclei and quantification of subnuclear spots using automated fluorescence mosaic microscopy, optimized image processing tools, and supervised classification. We demonstrate the efficiency of our analysis by determination of differential DNA damage repair patterns in response to genotoxic stress and radiation, and we show the potential of data mining in pinpointing specific phenotypes after transient transfection. The presented approach allowed for systematic analysis of subnuclear features in large image data sets and accurate classification of phenotypes at the level of the single cell. Consequently, this type of nuclear fingerprinting shows potential for high-throughput applications, such as functional protein assays or drug compound screening. ' 2009 International Society for Advancement of Cytometry

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“…Previously we reported that Si ion-induced DNA damage was repaired in a manner similar to repair of γ-ray-induced damage and that a larger fraction of Fe ion-induced DNA damage was irreparable (11). The difficulties associated with repair of DNA lesions induced by irradiation with Fe ions may be due to either the number of complex DNA lesions produced or the nature of clustered lesions induced.…”

Section: Resultsmentioning

confidence: 99%

Unrepaired clustered DNA lesions induce chromosome breakage in human cells

Asaithamby

Chen

2011

Proc. Natl. Acad. Sci. U.S.A.

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249

198

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Clustered DNA damage induced by ionizing radiation is refractory to repair and may trigger carcinogenic events for reasons that are not well understood. Here, we used an in situ method to directly monitor induction and repair of clustered DNA lesions in individual cells. We showed, consistent with biophysical modeling, that the kinetics of loss of clustered DNA lesions was substantially compromised in human fibroblasts. The unique spatial distribution of different types of DNA lesions within the clustered damages, but not the physical location of these damages within the subnuclear domains, determined the cellular ability to repair the damage. We then examined checkpoint arrest mechanisms and yield of gross chromosomal aberrations. Induction of nonrepairable clustered damage affected only G2 accumulation but not the early G2/M checkpoint. Further, cells that were released from the G2/M checkpoint with unrepaired clustered damage manifested a spectrum of chromosome aberrations in mitosis. Difficulties associated with clustered DNA damage repair and checkpoint release before the completion of clustered DNA damage repair appear to promote genome instability that may lead to carcinogenesis.heterochromatin | high linear energy transfer | high charge and energy particles | 53BP1 | ionizing radiation induced foci I onizing radiation (IR) may induce cancer and loss of neural function or death in humans. Low (e.g., γ-and X-rays) and high [i.e., high charge and energy (HZE)] linear energy transfer (LET) IR induces a plethora of DNA damage, and the damage complexity increases with an increase in the LET of the radiation (1-3). Isolated DNA lesions (mainly induced by low-LET radiation), including double-strand breaks (DSBs), single-strand breaks (SSBs), and damaged bases located at a distance from other damage, are generally repaired efficiently. Substantial evidence indicates that high-LET radiation induces complex DNA damage, a unique class of DNA lesions that includes two or more individual lesions within one or two helical turns of the DNA (4). These lesions can be abasic sites (apurinic/apyrimidinic sites or APs), damaged bases (oxidized purines or pyrimidines), SSBs, or DSBs (5). Convincing evidence indicates that complex DNA lesions are more difficult to repair than isolated lesions and in some instances are irreparable; however, it is unclear why clustered lesions are difficult to repair.The biological consequences of complex DNA damage range from point mutations and loss of genetic material to cellular lethality due to repair impairment and lesion or repair-intermediate persistency. Clustered lesions induce intra-and interchromosomal insertions, and inversions often in association with large deletions (6). FISH-painting methodologies were used to show that high-LET IR induces a high fraction of chromosome rearrangements (7). Recently, it has been suggested that non-DSB clusters, if unrepaired, can lead to the formation of mutations and chromosome abnormalities (8). After exposure to high-LET radiation, immortalized...

show abstract

Repair of HZE-Particle-Induced DNA Double-Strand Breaks in Normal Human Fibroblasts

Cited by 147 publications

References 44 publications

Stochastic Simulation of DNA Double-Strand Break Repair by Non-homologous End Joining Based on Track Structure Calculations

Stochastic Simulation of DNA Double-Strand Break Repair by Non-homologous End Joining Based on Track Structure Calculations

High content image cytometry in the context of subnuclear organization

Unrepaired clustered DNA lesions induce chromosome breakage in human cells

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