Low Doses Of Ionizing Radiation Research Articles

Mutation Induction in Cultured Human Cells after Low-dose and Low-dose-rate γ-ray Irradiation: Detection by LOH Analysis

To study the genetic effects of low-doses and low-dose-rate ionizing radiation (IR), human lymphoblastoid TK6 cells were exposed to 30 mGy of gamma-rays at a dose-rate of 1.2 mGy/hr. The frequency of early mutations (EMs) in the thymidine kinase (TK) gene locus was determined to be 1.7 x 10(-6), or 1.9-fold higher than the level seen in unirradated controls. These mutations were analyzed with a loss of heterozygosity (LOH) detection system, a methodology which has been shown to be sensitive to the effects of radiation. Among the 15 EMs observed after IR exposure, 8 were small interstitial-deletion events restricted to the TK gene locus. However, this specific type of event was not found in unirradiated controls. Although these results were observed under the limited conditions, they strongly suggest that the LOH detection system can be used for estimating the genetic effects of a low-dose IR exposure delivered at a low-dose-rate.

Combined low dose ionizing radiation and green tea-derived epigallocatechin-3-gallate treatment induces human brain endothelial cells death

The microvasculature of brain tumors has been proposed as the primary target for ionizing radiation (IR)-induced apoptosis. However, the contribution of low dose IR-induced non-apoptotic cell death pathways has not been investigated. This study aimed to characterize the effect of IR on human brain microvascular endothelial cells (HBMEC) and to assess the combined effect of epigallocatechin-3-gallate (EGCg), a green tea-derived anti-angiogenic molecule. HBMEC were treated with EGCg, irradiated with a sublethal (< or =10 Gy) single dose. Cell survival was assessed 48 h later by nuclear cell counting and Trypan blue exclusion methods. Cell cycle distribution and DNA fragmentation were evaluated by flow cytometry (FC), cell death was assessed by fluorimetric caspase-3 activity, FC and immunoblotting for pro-apoptotic proteins. While low IR doses alone reduced cell survival by 30%, IR treatment was found more effective in EGCg pretreated-cells reaching 70% cell death. Analysis of cell cycle revealed that IR-induced cell accumulation in G2-phase. Expression of cyclin-dependent kinase inhibitors p21(CIP/Waf1) and p27(Kip) were increased by EGCg and IR. Although random DNA fragmentation increased by approximately 40% following combined EGCg/IR treatments, the synergistic reduction of cell survival was not related to increased pro-apoptotic caspase-3, caspase-9 and cytochrome C proteins. Cell necrosis increased 5-fold following combined EGCg/IR treatments while no changes in early or late apoptosis were observed. Our results suggest that the synergistic effects of combined EGCg/IR treatments may be related to necrosis, a non-apoptotic cell death pathway. Strategies sensitizing brain tumor-derived EC to IR may enhance the efficacy of radiotherapy and EGCg may represent such a potential agent.

Extracellular matrix alterations in conventional renal cell carcinomas by tissue microarray profiling influenced by the persistent, long-term, low-dose ionizing radiation exposure in humans

The present study was carried out in order to examine molecular alterations of extracellular matrix (ECM), associated with cell-cell communication in conventional (clear-cell) renal cell carcinomas (cRCCs) influenced by persistent long-term, low-dose ionizing radiation (IR) exposure to patients living more than 19 years after the Chernobyl accident in Cesium 137 (137Cs)-contaminated areas of Ukraine. The ECM major components such as fibronectin, laminin, E-cadherin/beta-catenin complexes and p53 tumor suppressor gene protein, and transforming growth factor beta 1 (TGF-beta1) were immunohistochemically (IHC) evaluated in cRCCs from 59 Ukrainian patients, which represented 18 patients living in non-contaminated areas and 41 patients from 137Cs-contaminated areas. In contrast, a control group of 19 Spanish patients with analogue tumors were also investigated. For IHC evaluation, a tissue microarray technique was used. Decrease or loss and abnormal distribution of fibronectin, laminin, E-cadherin/beta-catenin complexes accompanied by elevated levels of p53 and TGF-beta1 were detected in the Ukrainian cRCCs from 137Cs-contaminated areas with statistically significant differences. Thus, our study suggests that chronic long-term, low-dose IR exposure might result in global remodeling of ECM components of the cRCCs with disruption in peri-epithelial stroma and epithelial basement membranes.

Low doses of ionizing radiation can prevent radiation-induced colonic epithelial hyporesponsiveness to muscarinic agonists

Purpose: Colonic epithelium hyporesponsiveness to different secretagogues occurs after exposure to ionizing radiation, increasing susceptibility to bacterial translocation and intraluminal toxins. Growing evidence suggests that the biological effects of radiation might be hormetic in nature. We investigated if exposure to low doses of ionizing radiation (LDR) can prevent colon hyposecretion due to subsequent larger doses.Methods: Rats were exposed to LDR (0.05 Gy) 24 h prior to 6 Gy, high dose radiation (HDR). The cyclic adenosine monophosphate (cAMP)-mediated pathway was explored using forskolin (FSK) and the intracellular Ca2+-mediated pathway through cholinergic stimulation. Changes in the colonic epithelium at the ultrastructural level were also explored.Results: Maximal short circuit current (Isc) response to carbachol was significantly reduced in the group exposed to 6 Gy HDR and this was completely prevented by prior exposure to LDR. Responses to both FSK and electrical field stimulation (EFS) were significantly reduced after HDR but they were not prevented by prior adaption of LDR. Hyposecretion was not prevented by the inducible nitric oxide synthase (iNOS) inhibitor L-N6-(l-iminoethyl)lysine (L-NIL) ruling out a role for iNOS-derived nitric oxide (NO) in the colonic hyposecretion associated with whole body radiation. Prior exposure to LDR diminished the deleterious effect of full HDR on the ultrastructure of colonic epithelium as colonocytes vacuolization, microvilli lost and separation between neighboring cells were less evident.Conclusions: Previous exposure to LDR can prevent intracellular Ca2+-mediated colonic hyposecretion associated with exposure to HDR but fails to modify cAMP-mediated hyposecretion. Morphological damage at the ultrastructural level is less evident after prior LDR.

DNA repair after low doses of ionising radiation

Exposure of mammalian cells to Ionising Radiation (IR) results in an integrated cellular response in which the activation of cell-cycle checkpoints is coordinated with DNA-repair pathways to optimise the removal of potentially cytotoxic or mutagenic DNA lesions. Radiobiological models have usually been based on observations of the cellular response to high doses of IR delivered acutely. This paper discusses how current models can accommodate responses to low dose or low dose-rate irradiation. In particular, the phenomena of low-dose hypersensitivity/induced radioresistance, adaptive responses and bystander effects all require reconsideration of these models. Questions addressed include: whether low doses of IR that are insufficient to activate induced radioresistance invoke DNA-repair responses less efficiently than doses that are above the threshold for this response; whether DNA-repair activity is induced by low (priming) doses of IR that activate the adaptive response; and how DNA-repair status influences the cells' response to bystander signals.

Differential Response Induced by Exposure to Low-Dose Ionizing Radiation in SHSY-5Y and Normal Human Fibroblast Cells

Radiation therapy has been used in the treatment of a wide variety of cancers for nearly a century and is one of the most effective ways to treat cancer. Low-dose ionizing radiation (IR) can interfere with cell division of cancer and normal cells by introducing oxidative stress and injury to DNA. The differences in the response to IR-induced DNA damage and increased reactive oxygen species between normal human fibroblasts (NHFs) and cancerous SHSY-5Y cells were considered. H2AX staining and comet assays revealed that NHF cells responded by initiating a DNA repair sequence whereas SHSY-5Y cells did not. In addition, NHF cells appeared to quench the oxidative stress induced by IR, and after 24 h no DNA damage was present. SHSY-5Y cells, however, did not repair their DNA, did not quench the oxidative stress, and showed characteristic signs that they were beginning to undergo apoptosis. These results indicate that there is a differential response between this cancerous and normal cell line in their ability to respond to low-dose IR, and these differences need to be exploited in order to treat cancer effectively. Further study is needed in order to elucidate the mechanism by which SHSY-5Y cells undergo apoptosis following radiation and why these normal cells are better equipped to deal with IR-induced double-strand breaks and oxidative stress.

DNA damage repair in bladder urothelium after the Chernobyl accident in Ukraine.

We determined whether base and nucleotide excision repair is activated in bladder urothelium by chronic persistent low doses of ionizing radiation in male patients with benign prostate hyperplasia and females with chronic cystitis living more than 15 years in Cs contaminated areas after the Chernobyl accident in Ukraine. Bladder urothelial biopsies from 204 patients were subjected to histological examination and biopsies from 35 were subjected to immunohistochemical study of 8-hydroxy-2'deoxyguanosine, 8-oxoguanine-DNA-glycosylase, apurinic/apyrimidinic endonuclease and xeroderma pigmentosum A endonuclease. Chronic proliferative atypical cystitis with multiple foci of dysplasia and carcinoma in situ were observed in 139 (89%) and in 91 (58%) of 156 group 1 patients from radio contaminated areas, respectively, as well as 10 small transitional cell carcinomas. Chronic cystitis with areas of dysplasia was detected in 9 of 48 patients (19%) in control group 2 from clean (without radio contamination) areas of Ukraine. Greatly elevated levels of 8-hydroxy-2'deoxyguanosine, 8-oxoguanine-DNA-glycosylase, apurinic/apyrimidinic endonuclease and xeroderma pigmentosum A were evident in the urothelium in group 1, accompanied by increased Cs in the urine. These findings support the hypothesis that significant activation of DNA damage repair (base and nucleotide excision repair) is induced by the oxidative stress generated by long-term low doses of ionizing radiation. The levels of DNA oxidative adducts pointing to mutagenic and carcinogenic potential were in line with the histopathologically diagnosed urothelial lesions.

Inhibition of the DNA-Dependent Protein Kinase Catalytic Subunit Radiosensitizes Malignant Glioma Cells by Inducing Autophagy

DNA-dependent protein kinase (DNA-PK) plays a major role in the repair of DNA double-strand breaks induced by ionizing radiation (IR). Lack of DNA-PK causes defective DNA double-strand break repair and radiosensitization. In general, the cell death induced by IR is considered to be apoptotic. On the other hand, nonapoptotic cell death, autophagy, has recently attracted attention as a novel response of cancer cells to chemotherapy and IR. Autophagy is a protein degradation system characterized by a prominent formation of double-membrane vesicles in the cytoplasm. Little is known, however, regarding the relationship between DNA-PK and IR-induced autophagy. In the present study, we used human malignant glioma M059J and M059K cells to investigate the role of DNA-PK in IR-induced apoptotic and autophagic cell death. Low-dose IR induced massive autophagic cell death in M059J cells that lack the catalytic subunit of DNA-PK (DNA-PKcs). Most M059K cells, the counterpart of M059J cells in which DNA-PKcs are expressed at normal levels, survived, and proliferated although a small portion of the cells underwent apoptosis. Low-dose IR inhibited the phosphorylation of p70(S6K), a molecule downstream of the mammalian target of rapamycin associated with autophagy in M059J cells but not in M059K cells. The treatment of M059K cells with antisense oligonucleotides against DNA-PKcs caused radiation-induced autophagy and radiosensitized the cells. Furthermore, antisense oligonucleotides against DNA-PKcs radiosensitized other malignant glioma cell lines with DNA-PK activity, U373-MG and T98G, by inducing autophagy. The specific inhibition of DNA-PKcs may be promising as a new therapy to radiosensitize malignant glioma cells by inducing autophagy.

Low dose radiation induced immunomodulation: Effect on macrophages and CD8+ T cells

Purpose: The aim of the present investigation was to study the effect of fractionated whole body low dose ionizing radiation (LDR) on the functional responses of T lymphocytes, their subpopulations and macrophages.Materials and methods: C57BL/6 mice were exposed to 4 cGy from a 60Co source, at 0.31 cGy/min, at 24 h intervals for 5 days (total dose 20 cGy). Phagocytic activity was measured by flow cytometry using Bioparticles® and nitric oxide generation was estimated by spectrophotometry. Proliferation of lymphocytes in response to concanavalin A (con A) and alloantigens was measured by 3H thymidine incorporation. Expression of cell surface markers was assessed by flow cytometric analysis of antibody labeled cells. Target cell killing by cytotoxic T cells (CTL) generated against allogenic cells was assessed by flow cytometry using PKH26 labeled target cells. Cytokines were estimated by enzyme linked immunosorbent assay.Results: Exposure to LDR enhanced nitric oxide secretion and phagocytosis. The expression of early activation antigen, CD69, was enhanced in CD8+ T lymphocytes concomitant with enhanced proliferation in response to con A. In addition, mixed lymphocyte reaction (MLR) and CTL response were augmented and secretion of interferon gamma (IFN-γ) was suppressed following LDR exposure.Conclusions: LDR exposure enhanced the function of macrophages and responses of CD8+ T cells in C57BL/6 mice.

Cell Cycle Regulators Modulating Con A Mitogenesis and Apoptosis in Low-Dose Radiation-Exposed Mice

Low doses of ionizing radiation (LDR) are reported to induce transient changes in mouse lymphocytes, such as enhanced response to polyclonal T cell mitogens, increased expression of heat shock proteins, and p53. We evaluated the role of cell cycle proteins and apoptosis in lymphocytes of C57BL/6 mice exposed to 20 cGy fractionated LDR. We found an enhanced cell proliferation in response to the mitogen concanavalin A (con A). The expression of several cell cycle and apoptosis-related intracellular and extracellular proteins was analyzed by flowcytometry following labeling with specific antibodies. An increased response to con A was accompanied by an increase in the expression of proliferating cell nuclear antigen (PCNA) and cyclins D and A. The expression of cyclin B did not change significantly. In 20 cGy-exposed C57BL/6 mice, the caspase activity and apoptosis were reduced in con A-stimulated spleen cells as compared to sham controls. The expression of Fas and Fas ligand was analyzed by labeling with specific antibodies followed by flowcytometry. There was no change in the expression of Fas and Fas ligand. The change in the mitochondrial transmembrane potential was followed by labeling the cells with the dye 5,5',6,6',-tetrachloro-1,1,3,3-tetraethylbenzimidazolcarbocyanine iodide (JC-I) and analyzing by flowcytometry. Mitochondrial stability was increased in spleen cells of LDR-treated mice. These data suggest that LDR induces augmentation of mitogenic response by modulation of expression of cyclins and the mitochondrial membrane potential leading to reduced apoptosis.

Mdc1 couples DNA double-strand break recognition by Nbs1 with its H2AX-dependent chromatin retention.

Mdc1/NFBD1 controls cellular responses to DNA damage, in part via interacting with the Mre11-Rad50-Nbs1 complex that is involved in the recognition, signalling, and repair of DNA double-strand breaks (DSBs). Here, we show that in live human cells, the transient interaction of Nbs1 with DSBs and its phosphorylation by ATM are Mdc1-independent. However, ablation of Mdc1 by siRNA or mutation of the Nbs1's FHA domain required for Mdc1 binding reduced the affinity of Nbs1 for DSB-flanking chromatin and caused aberrant pan-nuclear dispersal of Nbs1. This occurred despite normal phosphorylation of H2AX, indicating that lack of Mdc1 does not impair this DSB-induced chromatin change, but rather precludes the sustained engagement of Nbs1 with these regions. Mdc1 (but not Nbs1) became partially immobilized to chromatin after DSB generation, and siRNA-mediated depletion of H2AX prevented such relocalization of Mdc1 and uncoupled Nbs1 from DSB-flanking chromatin. Our data suggest that Mdc1 functions as an H2AX-dependent interaction platform enabling a switch from transient, Mdc1-independent recruitment of Nbs1 to DSBs towards sustained, Mdc1-dependent interactions with the surrounding chromosomal microenvironment.

Are Low Doses of Ionizing Radiation Hazardous to Young Children

High doses of ionizing radiation to the developing brain are known to cause significant cognitive impairment and even mental retardation, as shown in

Clusterin: a protein with multiple functions as a potential ionizing radiation exposure marker

Secretory clusterin (sCLU), a multifunctional glycoprotein, is induced in response to ionizing radiation (IR) at low and high doses. We are, therefore, developing a cellular biodosimetry system utilizing the CLU promoter-luciferase-neo® genetic construct and a bioluminescent imaging system (BLIS) for the real-time detection of CLU induction as a function of low doses of IR, using both tissue culture and animal systems. In order to develop such a biodosimeter, endogenous sCLU levels in tissues of animals must be characterized using Western blot analyses to ensure that the luciferase reporter gene induction matches induction responses, in terms of dose–responses and time-courses. Whole body 0.1–5 Gy gamma-irradiation of C57BL/6J mice induced CLU levels 2–3 days post-IR in thymus, spleen, and bone marrow. Interestingly, sCLU was not induced in liver, brain, or colon. These data indicate a tissue-specific, and a rather delayed time-course of sCLU induction, matching sCLU IR responses in human MCF-7:WS8 breast cancer cells in culture. To develop a biodosimeter, an MCF-7 1403 cell line expressing the luciferase gene regulated by the 1403 bp CLU promoter was generated, wherein CLU promoter expression mimicked the endogenous CLU gene. In contrast to standard luciferase assays using a luminometer, significant changes in CLU promoter expression in MCF-7 1403 cells were detected after 10 cGy using BLIS, which were comparable with endogenous sCLU protein expression. In summary, sCLU is induced in response to low-dose IR both in vitro using human tissue culture and in vivo in mouse proliferating tissues. Examination of CLU promoter-driven luciferase levels in irradiated MCF-7 1403 cells by BLIS is a promising approach for applications in biodosimetry.

Transcription factors activated in mammalian cells after clinically relevant doses of ionizing radiation.

Over the past 15 years, a wealth of information has been published on transcripts and proteins 'induced' (requiring new protein synthesis) in mammalian cells after ionizing radiation (IR) exposure. Many of these studies have also attempted to elucidate the transcription factors that are 'activated' (i.e., not requiring de novo synthesis) in specific cells by IR. Unfortunately, all too often this information has been obtained using supralethal doses of IR, with investigators assuming that induction of these proteins, or activation of corresponding transcription factors, can be 'extrapolated' to low-dose IR exposures. This review focuses on what is known at the molecular level about transcription factors induced at clinically relevant (< or =2 Gy) doses of IR. A review of the literature demonstrates that extrapolation from high doses of IR to low doses of IR is inaccurate for most transcription factors and most IR-inducible transcripts/proteins, and that induction of transactivating proteins at low doses must be empirically derived. The signal transduction pathways stimulated after high versus low doses of IR, which act to transactivate certain transcription factors in the cell, will be discussed. To date, only three transcription factors appear to be responsive (i.e. activated) after physiological doses (doses wherein cells survive or recover) of IR. These are p53, nuclear factor kappa B(NF-kappaB), and the SP1-related retinoblastoma control proteins (RCPs). Clearly, more information on transcription factors and proteins induced in mammalian cells at clinically or environmentally relevant doses of IR is needed to understand the role of these stress responses in cancer susceptibility/resistance and radio-sensitivity/resistance mechanisms.

Le Fort I osteotomy and low-dose rate Ir192 brachytherapy for treatment of recurrent nasopharyngeal tumours.

Treatment of recurrent nasopharyngeal carcinoma is a difficult clinical problem. External beam re-irradiation is associated with a long-term cure in a proportion of cases but this may be associated with severe radiation injury. Eighteen patients with post-nasal space tumours were treated between 1986 and 2001 with surgical excision and nasopharyngeal brachytherapy via a Le Fort I osteotomy approach. Low-dose rate (LDR) and high-dose rate (HDR) brachytherapy was used. Data was prospectively collected. Local control and overall survival were measured. Acute and late complications were assessed using the RTOG system. The overall survival was 67% at 2 years and 33.5% at 5 years. The corresponding local control rates were 42 and 31.5%, respectively. The T stage at relapse was a significant prognostic factor for local control (P=0.004) but not overall survival. Acute toxicity was mild. RTOG grade >/=3 late complications occurred in 40% of patients treated with the HDR, and 0% treated with LDR. The results of the Le Fort osteotomy, tumour debulking and post-operative brachytherapy gives local control rates similar to those achieved with wide-field re-irradiation. Complication rates are acceptable and are lower than that reported with other methods of radiation therapy. The surgical technique was well tolerated. HDR brachytherapy with this technique had a high complication rate. This approach is a viable option in the treatment of recurrent nasopharyngeal tumours.

Ionizing radiation potentiates the antitumor efficacy of oncolytic herpes simplex virus G207 by upregulating ribonucleotide reductase

Background. Replication-competent herpes simplex virus-1 (HSV-1) mutants have an oncolytic effect on human and animal cancers. The aim of this study was to determine whether G207, an HSV-1 mutant, can be combined with ionizing radiation (IR) to increase antitumor activity while decreasing treatment-associated toxicity. Methods. This study was performed by using G207, a replication-competent HSV-1 mutant deficient in viral ribonucleotide reductase (RR) and the γ134.5 neurovirulence protein. The antitumor activity of G207 or IR was tested against HCT-8 human colorectal cancer cells in vitro and in an in vivo mouse subcutaneous tumor model. Results. We demonstrated that G207 has significant oncolytic effect on HCT-8 cells in vitro in a cytotoxicity assay and in vivo in a mouse flank tumor model and that these effects are improved with low-dose IR. We further illustrated that the increased tumoricidal effect is dependent on the up-regulation of cellular RR by IR measured by a functional bioassay for RR activity. Chemical inhibition of RR by hydroxyurea abrogates the enhanced effect. In contrast to G207, R3616, the parent virus of G207 that expresses functional RR, does not exhibit enhanced oncolysis when combined with IR. Conclusions. These data encourage clinical investigation of combination radiation therapy and HSV oncolytic therapy. (Surgery 2002;132:353-9.)

Mutation induction in human cells after low dose X ray exposure.

Mutations induced after low dose ionising radiation exposure have been intensively analysed not only for radiation risk estimation but also for basic understanding of cellular responses. Human lymphoblastoid TK6-20C cells were irradiated with 100 mGy of X rays and mutation at the heterozygous thymidine kinase (TK) locus was selected by trifluorothymidine (TFT) resistance. Although the mutation frequency at the TK locus increased from 5.6 x 10(-6) to 7.4 x 10(-6), this increase was not statistically significant. However, molecular analysis of TK mutants exhibiting loss of heterozygocity (LOH) demonstrated a clear effect of such low dose IR exposure. Exposure to 100 mGy X ray increased the fraction of hemizygous-LOH from 10% to 42%. In previous experiments, a similar tendency in the increase of hemizygous-LOH was also observed in TK6 cells after exposure to a 2 Gy dose of X rays. This type of LOH can be considered as a result of end-joining repair of DNA double strand breaks.

Linear Dose–Effect Relation for Radiation and Chemical Carcinogenic Risk

It is often asserted in the literature that a linear dose–effect relation at low ionizing radiation doses overestimates the radiation risk. It is shown by means of a simple mathematical analysis that this assertion is incorrect with respect to an individual source of radiation or chemical action, acting against the background of other endogenic (internal) and exogenic factors giving rise to cancer. In reality, the risk can be underestimated: if a sublinear relation is valid for the total carcinogenic risk, then an epidemiological study of an individual source of ionizing radiation or chemical action can yield a superlinear relation. For a sublinear total dose–effect relation, a specific source of carcinogenic action cannot be estimated separately. The sum of all endogenic and exogenic sources of such action moves the effect out of the low dose range. Consequently, it is recommended that a linear relation be applied to a specific source of carcinogenesis. In so doing such an estimate should not be viewed as too high (upper limit). The same considerations are also valid for the dose rate dependence.

Ionizing radiation and mitogenetic radiation: two links of the same energetic chain in a biological cell

Present research demonstrates that the excitation of living systems by high energy/low doses of ionizing radiation (IR) initiates prolonged secondary ultraviolet (UV) range emission that influences biota. When doses of this energy are too high, the process of energy or radiation absorption by the cells causes negative changes (i.e. negative mutations or death). When these doses are sufficiently low, vital processes inside the cells are stimulated and can create positive changes. This paper proposes a common denomination for mechanisms of UV and ionizing radiation when interacting with living cells, underlying both its mitogenetic effect and radiation hormesis. Data from radon exposure in chronically exposed nuclear workers, acutely exposed Hiroshima and Nagasaki victims and observers of atmospheric nuclear explosions, combined with animal results, present irrefutable evidence that low doses of IR are beneficial. As a conclusion the author postulates the possibility of new methods of therapy regarding the use of IR and mitogenetic radiation. This paper has been written to encourage debate regarding possible future benefits that may be derived from low level doses of IR exposure in the general population.

Histone H1 Dephosphorylation Is Mediated through a Radiation-induced Signal Transduction Pathway Dependent on ATM

Ionizing radiation is known to activate multiple signal transduction pathways, but the targets of these pathways are poorly understood. Phosphorylation of histone H1 is thought to have a role in chromatin condensation/decondensation, and we asked whether ionizing radiation (IR) would alter H1 phosphorylation. Our data demonstrate that low doses of IR result in a dramatic, but transient, dephosphorylation of H1 isoforms. The in vivo IR-induced dephosphorylation of H1 is completely blocked by wortmannin and is abrogated in ataxia telangiectasia cells. Furthermore, we measured radiation-induced inhibition of cyclin dependent kinase activity and activation of histone H1 phosphatase activity. Both activities were affected by radiation-induced signals in an ATM-dependent manner. Thus, the rapid IR-induced dephosphorylation of H1 involves a pathway including ATM and a wortmannin-sensitive step leading to both inhibition of cyclin-dependent kinase activities as well as activation of H1 phosphatase(s).