Evasion of Early Cellular Response Mechanisms following Low Level Radiation-induced DNA Damage

Collis, Spencer J.; Schwaninger, Julie M.; Ntambi, Alfred J.; Keller, Thomas W.; Nelson, William G.; Dillehay, Larry E.; DeWeese, Theodore L.

doi:10.1074/jbc.m409600200

Cited by 133 publications

(79 citation statements)

References 37 publications

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“…Sensing of the induced DNA damage of replicating mammalian cells depends on the rate at which this damage is delivered, as has been directly demonstrated by DeWeese and colleagues (14).…”

Section: Parabolic Relationship Of Biological Effects To Drmentioning

confidence: 86%

“…From these and other recent data (14-16), we conclude that different mammalian cell lines show a parabolic dependence of the loss of clonogenic survival [per given dose of 5 sieverts (Sv)] on DR. The reproductive cell death (lethality) for human PC3 prostate cancer cells was decreased as the DR was decreased from 55 cSv͞min to 1.8 cSv͞min, but there is an inverse DRE with increase in lethality as the DR was decreased further from Ϸ1 to 0.03 cSv͞min ( It is established that DSBs and errors in their repair are responsible for most, if not all, IR-induced lethality (14,(17)(18)(19) and are major factors in mutagenesis (8,20). The close relationship between the above parabolic curves for lethality͞ inactivation and for somatic mutation suggests to us that DSBs, both endogenous and IR-induced, may be limiting factors for both DR processes.…”

Section: Somatic Mutationsmentioning

confidence: 99%

“…As noted above, the proteins ATM and H2AX are important for recognition of both induced DSBs and EDSBs, as are some other components in the DSB repair process, e.g., the complex of RAD50, MRE11, and NBS1 proteins, which are shared by homologous recombination repair and nonhomologous end joining. It is interesting that Collis et al (14) found that interactions between NBS1 and ATM are compromised at very low DRs of IR, with considerable reduction of levels of ␥-H2AX-marked DSBs. This conclusion is also consistent with the report of Rothkamm and Lobrich (32) that failure of DSB repair can occur at a very low dose of IR (1 mGy).…”

Section: Parabolic Relationship Of Biological Effects To Drmentioning

confidence: 99%

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Radiation dose-rate effects, endogenous DNA damage, and signaling resonance

Vilenchik

Knudson

2006

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

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We previously concluded, from our analysis of the published data of other investigators, that the yield of germ-line and somatic mutations after exposure to ionizing radiation is parabolically related to the logarithm of the dose-rate at which a given dose is administered. Here we show that other data reveal a similarly parabolic relationship for other ionizing radiation-associated phenomena, namely, genetic recombination, chromosomal translocation, cell inactivation and lethality, and human leukemogenesis. Furthermore, the minima for all effects fall in a relatively narrow range of the dose-rate logarithms. Because the only mechanism common to all of these phenomena is the double-strand break (DSB) in DNA, we refer to our previous analysis of the endogenous production of DSBs, from which we concluded that Ϸ50 endogenous DSBs occur per cell cycle, although most are repaired without error. Comparison then reveals that their rate of production falls within the range of minima for the several end points pursuant to radiation-induced DSBs. We conclude that the results reflect a physiological principle whereby signals originating from induced DSBs elicit responses of maximal effectiveness when they are produced at a rate near that of the production of endogenous DSBs. We refer to this principle as ''signaling resonance.'' DNA repair ͉ mutilation ͉ repair ͉ leukemogenesis ͉ parabolic minimum T he mutagenic and carcinogenic effects of sparsely ionizing radiation (IR), such as x-rays or ␥-rays, decrease for a given dose as the dose-rate (DR) is decreased in the range of 1-100 centisieverts (cSv)͞min, a phenomenon known as the direct DR effect (DRE) and attributed to increasingly effective repair of DNA damage. On the basis of observations on locus-specific germ-line mutations in mouse spermatogonial stem cells, Lyon concluded that there could be an increase in mutation rates below this DR, with a minimum rate of damage near 0.1 cSv͞min (reviewed in ref. 1), but this conclusion was not generally accepted. Our analysis of available data for both germ-line and somatic mutations demonstrated that this inverse DRE is characteristic and that the overall DREs are parabolic functions of the logarithms of DRs over a range of approximately six logs, with minimal mutation rates per unit of dose in the range of 0.03-1.0 cSv͞min (1). This finding then raises the question of why the minimum occurs in this range, far above a common rate of background radiation on the order of 10 Ϫ7 cSv͞min.Here we analyze published data on both mutation and other radiation genetic endpoints not only for the existence of DREs, but also for clues to a mechanistic explanation. Such studies have been published for somatic recombination, for chromosomal translocations, for cell inactivation and lethality, and for human leukemogenesis. Because all of these phenomena can involve double-strand breaks (DSBs) in DNA, we compare the results of all of the DREs with those of our previous analysis of the spontaneous production of endogenous DSBs (EDSBs) (2) in an a...

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“…Sensing of the induced DNA damage of replicating mammalian cells depends on the rate at which this damage is delivered, as has been directly demonstrated by DeWeese and colleagues (14).…”

Section: Parabolic Relationship Of Biological Effects To Drmentioning

confidence: 86%

Section: Somatic Mutationsmentioning

confidence: 99%

Section: Parabolic Relationship Of Biological Effects To Drmentioning

confidence: 99%

See 1 more Smart Citation

Radiation dose-rate effects, endogenous DNA damage, and signaling resonance

Vilenchik

Knudson

2006

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

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“…An absence of c-H2AX or inhibition of the phosphorylation of H2AX enhanced sensitivity to radiation [23,24]. We assumed two patterns of correlation between cell death and induction of c-H2AX on exposure to ionizing radiation; a linear-model, in which cells are killed depending on the dose of radiation, and levels of c-H2AX increase similarly [25,26], and a non-linear-model, in which cell death and c-H2AX induction are not completely interrelated [24]. In our study, the correlation was non-linear.…”

Section: Discussionmentioning

confidence: 99%

Coexposure to benzo[a]pyrene and UVA induces phosphorylation of histone H2AX

Toyooka

Ibuki

2005

FEBS Letters

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Phosphorylation of histone H2AX (termed c-H2AX) was recently identified as an early event after induction of DNA double strand breaks (DSBs). We have previously shown that coexposure to benzo[a]pyrene (BaP), a wide-spread environmental carcinogen, and ultraviolet A (UVA), a major component of solar UV radiation, induced DSBs in mammalian cells. In the present study, we examined whether coexposure to BaP and UVA generates c-H2AX in CHO-K1 cells. Single treatment with BaP (10 À9-10 À7 M) or UVA ($2.4 J/cm 2 ) did not result in c-H2AX, however, coexposure drastically induced foci of c-H2AX in a dose-dependent manner. c-H2AX could be detected even at very low concentration of BaP (10 À9 M) plus UVA (0.6 J/cm 2 ), which did not change cell survival rates. NaN 3 effectively inhibited the formation of c-H2AX induced by coexposure, indicating the contribution of singlet oxygen. This is the first evidence that coexposure to BaP and UVA induced DSBs, involving c-H2AX.

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“…The Arg allele of the TP53 Arg72ProSNP is more efficient in inducing apoptosis while the Pro allele induces more G 1 arrest and is better at activation of TP53-dependent DNA repair (3,55,56). Depending on the severity of the damage, cells may either choose to arrest the cell cycle until the damage is repaired, or if the damage is irreparable, proceed to apoptosis (57,58). As the balance between cell cycle arrest/DNA repair and apoptosis is adequate to allow error-free repair or apoptotic removal of a heavily damaged genome, our study population might not be heavily exposed to exogenous carcinogens.…”

Section: ------------------------------------------------------------mentioning

confidence: 99%

Cigarette smoking, TP53 Arg72Pro, TP53BP1 Asp353Glu and the risk of lung cancer in a Japanese population

Kiyohara¹

2010

Oncol Rep

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Abstract. The tumor suppressor protein p53 (TP53) plays a central role in directing cellular responses to DNA damage. Tumor protein 53-binding protein 1 (TP53BP1) binds to TP53 and has a potential role in DNA damage responses. DNA damage-dependent interaction between TP53 and TP53BP1 may contribute to lung cancer risk. We aimed to assess whether or not TP53 and TP53BP1 genetic polymorphisms modulate lung cancer susceptibility in a Japanese population. We investigated the relationship of the TP53 Arg72Pro and TP53BP1 Asp353Glu polymorphisms to lung cancer risk with special reference to polymorphism-polymorphism and polymorphism-smoking interactions among 462 lung cancer cases and 379 controls. The Glu/Glu genotype of TP53BP1 Asp353Glu polymorphism was associated with a decreased risk of lung cancer [odds ratio (OR) = 0.46, 95% confidence interval (CI) = 0.29-0.74]. There was no polymorphism-smoking interaction. A combination of the Pro allele carriage of the TP53 Arg72Pro polymorphism and the Glu/Glu genotype of the TP53BP1 Asp353Glu polymorphism was associated with a decreased risk of lung cancer (OR=0.38, 95% CI=0.17-0.83). The multiplicative interaction measure was statistically significant (OR for interaction = 2.93, 95% CI=1.24-6.93). The relative excess risk due to interaction and attributable proportion due to interaction were 0.74 (95% CI=0.38-1.20) and 0.63 (95% CI=0.05-1.21), respectively. Both the additive interaction measures were not equal to zero, suggesting that the existence of a biological interaction. Our findings indicate the possible association of the Glu allele of the TP53BP1 Asp353Glu polymorphism with lower risk of lung cancer especially among the Pro allele carriers of the TP53 Arg72Pro polymorphism.

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Evasion of Early Cellular Response Mechanisms following Low Level Radiation-induced DNA Damage

Cited by 133 publications

References 37 publications

Radiation dose-rate effects, endogenous DNA damage, and signaling resonance

Radiation dose-rate effects, endogenous DNA damage, and signaling resonance

Coexposure to benzo[a]pyrene and UVA induces phosphorylation of histone H2AX

Cigarette smoking, TP53 Arg72Pro, TP53BP1 Asp353Glu and the risk of lung cancer in a Japanese population

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