Toxicity from radiation therapy associated with abnormal transcriptional responses to DNA damage.
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ABSTRACT:
SUBMITTER: Rieger KE
PROVIDER: S-EPMC404097 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Peripheral blood lymphocytes from a total of 57 patients were immortalized with Epstein-Barr virus. Fourteen radiation-therapy patients suffered unusual levels of radiation toxicity (RadS). Thirteen radiation-therapy patients with limited toxicity (RadC) were enrolled as controls. Fifteen patients diagnosed with skin cancer before age 40 (SkCa) were used as a second group of controls. Fifteen healthy subjects without any history of cancer (NoCa) were matched to the skin cancer patients and used as a third group of controls. Cells were exposed to mock treatment (Mock), ultra-violet radiation (UV), or ionizing radiation (IR). For UV radiation treatment, cells were exposed to 10 J/m^2 and harvested for RNA 24 hours later. For IR treatment, cells were exposed to 5 Gy of IR and harvested for RNA 4 hours later. For example, RadS1-Mock refers to cells from radiation sensitive patient 1 exposed to mock treatment. The published manuscript (PNAS 101:6634, 2004) can be found at http://www.pnas.org/cgi/doi/10.1073/pnas.0307761101 Data were analyzed with Affymetrix MAS version 4.0. Normalization – A reference data set was generated by averaging the expression of each gene over all data sets. The data for each hybridization were compared with the reference data set in a cube root scatter plot. A linear least-squares fit to the cube root scatter plot was then used to normalize each hybridization. Keywords = Gene expression in lymphoid cells of cancer patients Keywords: repeat sample
2004-09-06 | GSE1725 | GEO
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Project description:RB plays an essential role in DNA damage-induced growth arrest and regulates the expression of several factors essential for DNA repair machinery. However, how RB coordinates DNA damage response through transcriptional regulation of genes involved in growth arrest remains largely unexplored. We examined whether RB can mediate the response to DNA damage through modulation of ZBRK1, a zinc finger-containing transcriptional repressor that can modulate the expression of GADD45A, a DNA damage response gene, to induce cell cycle arrest in response to DNA damage. We found that the ZBRK1 promoter contains an authentic E2F-recognition sequence that specifically binds E2F1, but not E2F4 or E2F6, together with chromatin remodeling proteins CtIP and CtBP to form a repression complex that suppresses ZBRK1 transcription. Furthermore, loss of RB-mediated transcriptional repression led to an increase in ZBRK1 transcript levels, correlating with increased sensitivity to ultraviolet (UV) and methyl methanesulfonate-induced DNA damage. Taken together, these results suggest that the RB·CtIP (CtBP interacting protein)/CtBP (C terminus-binding protein) /E2F1 complex plays a critical role in ZBRK1 transcriptional repression, and loss of this repression may contribute to cellular sensitivity of DNA damage, ultimately leading to carcinogenesis.
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Project description:The molecular basis for p53-mediated tumor suppression remains unclear. Here, to elucidate mechanisms of p53 tumor suppression, we use knockin mice expressing an allelic series of p53 transcriptional activation mutants. Microarray analysis reveals that one mutant, p53(25,26), is severely compromised for transactivation of most p53 target genes, and, moreover, p53(25,26) cannot induce G(1)-arrest or apoptosis in response to acute DNA damage. Surprisingly, p53(25,26) retains robust activity in senescence and tumor suppression, indicating that efficient transactivation of the majority of known p53 targets is dispensable for these pathways. In contrast, the transactivation-dead p53(25,26,53,54) mutant cannot induce senescence or inhibit tumorigenesis, like p53 nullizygosity. Thus, p53 transactivation is essential for tumor suppression but, intriguingly, in association with a small set of novel p53 target genes. Together, our studies distinguish the p53 transcriptional programs involved in acute DNA-damage responses and tumor suppression-a critical goal for designing therapeutics that block p53-dependent side effects of chemotherapy without compromising p53 tumor suppression.
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Project description:Research indicates that the transient contamination of DNA with ribonucleotides exceeds all other known types of DNA damage combined. The consequences of ribose incorporation into DNA, and the identity of protein factors operating in this RNA-DNA realm to protect genomic integrity from RNA-triggered events are emerging. Left unrepaired, the presence of ribonucleotides in genomic DNA impacts cellular proliferation and is associated with chromosome instability, gross chromosomal rearrangements, mutagenesis, and production of previously unrecognized forms of ribonucleotide-triggered DNA damage. Here, we highlight recent findings on the nature and structure of DNA damage arising from ribonucleotides in DNA, and the identification of cellular factors acting in an RNA-DNA damage response (RDDR) to counter RNA-triggered DNA damage.
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Project description:Fungi transcriptionally upregulate expression of azole efflux pumps and ergosterol biosynthesis pathway genes when exposed to antifungal agents that target ergosterol biosynthesis. To date, these transcriptional responses have been shown to be dependent on the presence of the azoles and/or depletion of ergosterol. Using an inducible promoter to regulate Neurospora crassa erg11, which encodes the major azole target, sterol 14?-demethylase, we were able to demonstrate that the CDR4 azole efflux pump can be transcriptionally activated by ergosterol biosynthesis inhibition even in the absence of azoles. By analyzing ergosterol deficient mutants, we demonstrate that the transcriptional responses by cdr4 and, unexpectedly, genes encoding ergosterol biosynthesis enzymes (erg genes) that are responsive to azoles, are not dependent on ergosterol depletion. Nonetheless, deletion of erg2, which encodes C-8 sterol isomerase, also induced expression of cdr4. Deletion of erg2 also induced the expression of erg24, the gene encoding C-14 sterol reductase, but not other tested erg genes which were responsive to erg11 inactivation. This indicates that inhibition of specific steps of ergosterol biosynthesis can result in different transcriptional responses, which is further supported by our results obtained using different ergosterol biosynthesis inhibitors. Together with the sterol profiles, these results suggest that the transcriptional responses by cdr4 and erg genes are associated with accumulation of specific sterol intermediate(s). This was further supported by the fact that when the erg2 mutant was treated with ketoconazole, upstream inhibition overrode the effects by downstream inhibition on ergosterol biosynthesis pathway. Even though cdr4 expression is associated with the accumulation of sterol intermediates, intra- and extracellular sterol analysis by HPLC-MS indicated that the transcriptional induction of cdr4 did not result in efflux of the accumulated intermediate(s). This study demonstrates, by detailed genetic and chemical analysis, that transcriptional responses by a major efflux pump and genes of the ergosterol biosynthesis pathway to ergosterol biosynthesis inhibitors can be independent of the presence of the drugs and are linked with the accumulation of ergosterol intermediate(s).
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Project description:EGFR signaling has been implicated in hypoxia-associated resistance to radiation or chemotherapy. Non-small cell lung carcinomas (NSCLC) with activating L858R or ?E746-E750 EGFR mutations exhibit elevated EGFR activity and downstream signaling. Here, relative to wild-type (WT) EGFR, mutant (MT) EGFR expression significantly increases radiosensitivity in hypoxic cells. Gene expression profiling in human bronchial epithelial cells (HBEC) revealed that MT-EGFR expression elevated transcripts related to cell cycle and replication in aerobic and hypoxic conditions and downregulated RAD50, a critical component of nonhomologous end joining and homologous recombination DNA repair pathways. NSCLCs and HBEC with MT-EGFR revealed elevated basal and hypoxia-induced ?-H2AX-associated DNA lesions that were coincident with replication protein A in the S-phase nuclei. DNA fiber analysis showed that, relative to WT-EGFR, MT-EGFR NSCLCs harbored significantly higher levels of stalled replication forks and decreased fork velocities in aerobic and hypoxic conditions. EGFR blockade by cetuximab significantly increased radiosensitivity in hypoxic cells, recapitulating MT-EGFR expression and closely resembling synthetic lethality of PARP inhibition.Implications: This study demonstrates that within an altered DNA damage response of hypoxic NSCLC cells, mutant EGFR expression, or EGFR blockade by cetuximab exerts a synthetic lethality effect and significantly compromises radiation resistance in hypoxic tumor cells. Mol Cancer Res; 15(11); 1503-16. ©2017 AACR.
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Project description:Stereotactic body radiation therapy (SBRT) is a technically demanding prostate cancer treatment that may be less expensive than intensity-modulated radiation therapy (IMRT). Because SBRT may deliver a greater biologic dose of radiation than IMRT, toxicity could be increased. Studies comparing treatment cost to the Medicare program and toxicity are needed.We performed a retrospective study by using a national sample of Medicare beneficiaries age ? 66 years who received SBRT or IMRT as primary treatment for prostate cancer from 2008 to 2011. Each SBRT patient was matched to two IMRT patients with similar follow-up (6, 12, or 24 months). We calculated the cost of radiation therapy treatment to the Medicare program and toxicity as measured by Medicare claims; we used a random effects model to compare genitourinary (GU), GI, and other toxicity between matched patients.The study sample consisted of 1,335 SBRT patients matched to 2,670 IMRT patients. The mean treatment cost was $13,645 for SBRT versus $21,023 for IMRT. In the 6 months after treatment initiation, 15.6% of SBRT versus 12.6% of IMRT patients experienced GU toxicity (odds ratio [OR], 1.29; 95% CI, 1.05 to 1.53; P = .009). At 24 months after treatment initiation, 43.9% of SBRT versus 36.3% of IMRT patients had GU toxicity (OR, 1.38; 95% CI, 1.12 to 1.63; P = .001). The increase in GU toxicity was due to claims indicative of urethritis, urinary incontinence, and/or obstruction.Although SBRT was associated with lower treatment costs, there appears to be a greater rate of GU toxicity for patients undergoing SBRT compared with IMRT, and prospective correlation with randomized trials is needed.
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Project description:DNA damage caused by UV radiation initiates cellular recovery mechanisms, which involve activation of DNA damage response pathways, cell cycle arrest and apoptosis. To assess cellular transcriptional responses to UVC-induced DNA damage we compared time course responses of human skin fibroblasts to low and high doses of UVC radiation known to induce a transient cellular replicative arrest or apoptosis, respectively. UVC radiation elicited >3-fold changes in 460 out of 12,000 transcripts and 89% of these represented downregulated transcripts. Only 5% of the regulated genes were common to both low and high doses of radiation. Cells inflicted with a low dose of UVC exhibited transcription profiles demonstrating transient regulation followed by recovery, whereas the responses were persistent after the high dose. A detailed clustering analysis and functional classification of the targets implied regulation of biologically divergent responses and suggested involvement of transcriptional and translational machinery, inflammatory, anti-proliferative and anti-angiogenic responses. The data support the notion that UVC radiation induces prominent, dose-dependent downregulation of transcription. However, the data strongly suggest that transcriptional repression is also target gene selective. Furthermore, the results demonstrate that dose-dependent induction of cell cycle arrest and apoptosis by UVC radiation are transcriptionally highly distinct responses. Keywords: other
2003-10-08 | GSE713 | GEO
Project description:We explored transcriptional responses of the fission yeast Schizosaccharomyces pombe to DNA damage. RNA-seq was used to characterize changes in expression profiles of all known lncRNAs and mRNAs in response to four DNA damage agents: Camptothecin, Hydroxyurea, Methyl methanesulfonate, Phleomycin.
2024-03-04 | GSE168230 | GEO