Radiation-induced genomic instability and its implications for radiation carcinogenesis

Huang, Lei; Snyder, Andrew R.; Morgan, William F.

doi:10.1038/sj.onc.1206697

Cited by 186 publications

(133 citation statements)

References 76 publications

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“…Another well-documented example of genetic instability found in mammalian cells occurs at a delayed time after exposure to ionizing radiation (16,17). This delayed or persistent chromosomal instability can occur in vitro or in vivo and is characterized by the appearance of new chromosome translocations and rearrangements for many generations after an initial exposure to ionizing radiation (18,19). It is currently not known whether the translocation instability that is associated with cancer cells and the delayed chromosomal instability observed in irradiated cells are caused by similar or distinct mechanisms.…”

Section: Discussionmentioning

confidence: 99%

Ionizing Radiation Induces Frequent Translocations with Delayed Replication and Condensation

Breger¹,

Smith²,

Turker

et al. 2004

Cancer Research

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Certain chromosome rearrangements display a significant delay in replication timing that is associated with a delay in mitotic chromosome condensation. Chromosomes with delay in replication timing/delay in mitotic chromosome condensation participate in frequent secondary rearrangements, indicating that cells with delay in replication timing/delay in mitotic chromosome condensation display chromosomal instability. In this report, we show that exposing cell lines or primary blood lymphocytes to ionizing radiation results in chromosomes with the delay in replication timing/delay in mitotic chromosome condensation phenotype, and that the delay in replication timing/delay in mitotic chromosome condensation phenotype occurs predominantly on chromosome translocations. In addition, exposing mice to ionizing radiation also induces cells with delay in replication timing/delay in mitotic chromosome condensation chromosomes that persist for as long as 2 years. Cells containing delay in replication timing/delay in mitotic chromosome condensation chromosomes frequently display hyperdiploid karyotypes, indicating that delay in replication timing/delay in mitotic chromosome condensation is associated with aneuploidy. Finally, using a chromosome engineering strategy, we show that only a subset of chromosome translocations displays delay in replication timing/delay in mitotic chromosome condensation. Our results indicate that specific chromosome rearrangements result in the generation of the delay in replication timing/delay in mitotic chromosome condensation phenotype and that this phenotype occurs frequently in cells exposed to ionizing radiation both in vitro and in vivo.

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Section: Discussionmentioning

confidence: 99%

Ionizing Radiation Induces Frequent Translocations with Delayed Replication and Condensation

Breger¹,

Smith²,

Turker

et al. 2004

Cancer Research

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“…For HZE nuclei such a fundamental question is complicated by what are the consequences of the early events that are already known to be different from X-rays (see Figure 3) and do they lead to an alien architecture on the voyage to malignancy? Tissue effects independent of DNA damage that have been associated with cancer initiation or progression include genomic instabilityP [64][65][66][67][68] P, extracellular matrix remodeling [69][70] , persistent inflammation [71][72] , and oxidative damage [73][74] . HZE nuclei will likely modify these responses, along with DNA changes, in ways distinct from other radiation types or carcinogens complicating our ability to estimate and mitigate risks.…”

Section: Cat and Mouse Game Or Little Green Men?mentioning

confidence: 99%

Heavy ion carcinogenesis and human space exploration

Durante¹,

Cucinotta²

2008

Nat Rev Cancer

522

324

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Prior to the human exploration of Mars or long duration stays on the Earth's moon, the risk of cancer and other diseases from space radiation must be accurately estimated and mitigated. Space radiation, comprised of energetic protons and heavy nuclei, has been show to produce distinct biological damage compared to radiation on Earth, leading to large uncertainties in the projection of cancer and other health risks, while obscuring evaluation of the effectiveness of possible countermeasures. Here, we describe how research in cancer radiobiology can support human missions to Mars and other planets. Introduction:

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“…How multiple mutations accumulate in the irradiated cells over a clinically relevant time period remains unclear. It was therefore suggested that ongoing genomic instability could result in the accumulation of mutations over a certain period of time after irradiation which, together with mutations directly induced in the irradiated cells, may significantly enhance radiation carcinogenesis [Huang et al, 2003;Goldberg, 2003]. In addition, the data on elevated mutation rates detected in the offspring of irradiated parents indicate a potential contribution of genomic instability to transgenerational carcinogenesis [Dubrova et al, 2000;Barber et al, 2002;.…”

Section: Introductionmentioning

confidence: 95%

“…The clinical implications of radiation-induced genomic instability, particularly its potential contribution to stepwise tumour progression, have been addressed in numerous publications [Huang et al, 2003;Goldberg, 2003]. Carcinogenesis is a multistep process in which somatic cells acquire mutations in a specific clonal lineage [Loeb et al, 2003].…”

Section: Introductionmentioning

confidence: 99%

Paternal exposure to ethylnitrosourea results in transgenerational genomic instability in mice

Dubrova

Hickenbotham

Glen

et al. 2008

Environ and Mol Mutagen

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Recent data show that the effects of ionising radiation are not restricted to the directly exposed parental germ cells, but can also manifest in their non-exposed offspring, resulting in elevated mutation rates and cancer predisposition. The mechanisms underlying these transgenerational changes remain poorly understood. One of the most important steps in elucidating these mechanisms is to investigate the initial cellular events that trigger genomic instability. Here we have analysed the effects of paternal treatment by ethylnitrosourea, an alkylating agent which is known to form specific types of DNA adducts, on the transgenerational effects in the first-generation (F 1 ) offspring of exposed CBA/Ca and BALB/c male mice. Mutation rates at two expanded simple tandem repeat loci were significantly elevated in the F 1 germline of both strains. Pre-and post-meiotic exposures resulted in similar increases in mutation rate in the F 1 germline. Within each strain mutation rates were equally elevated in the germline of male and female F 1 offspring of the directly exposed males. The results of our study suggest that transgenerational instability is not attributed to a specific sub-set of DNA lesions, such as double strand breaks, and is most probably triggered by a stress-like response to a generalised DNA damage.2

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Radiation-induced genomic instability and its implications for radiation carcinogenesis

Cited by 186 publications

References 76 publications

Ionizing Radiation Induces Frequent Translocations with Delayed Replication and Condensation

Ionizing Radiation Induces Frequent Translocations with Delayed Replication and Condensation

Heavy ion carcinogenesis and human space exploration

Paternal exposure to ethylnitrosourea results in transgenerational genomic instability in mice

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