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NFATC2 modulates radiation toxicity in dermal fibroblasts from patients with severe side-effects of radiotherapy

ABSTRACT: Although it is well established that 5 to 15% of radiotherapy patients exhibit severe side-effects in healthy tissue, the cellular and molecular mechanisms involved are still poorly known, and the link between cellular and tissue radiosensitivity is still debated. We here studied fibroblasts from normal skin of patients with severe sequels of radiotherapy in order to examine if specific basal cell activities might be involved in susceptibility to side-effects. When compared to control cells, patient fibroblasts exhibited higher radiosensitivity and defects in DNA double strand breaks (DSB) repair and 8-oxoGuanines, abasic sites and glycol damaged base repair. Transcriptome profiling of dermal fibroblast cell strains from 16 radiotherapy patients with severe side-effects and 8 healthy individuals identified 540 genes specifically deregulated in the patients. Nuclear factor of activated T cells 2 (NFATC2) was one of the most differentially expressed genes. This transcription factor involved in immune responses was found poorly expressed at transcript and protein level in patient cells, whereas the NFATC2 gene region was hypermethylated. Furthermore, NFATC2 expression correlated to the cell survival after irradiation. Finally, we observed that the silencing of NFATC2 in normal cells by RNA interference leads to increased cellular radiosensivity and defects in DNA DSB repair. This study demonstrates that patients with clinical hypersensitivity also exhibit intrinsic cellular radiosensitivity in normal skin cells. It further reveals a new role for NFATC2 as a potential regulator of the cellular sensitivity to ionizing radiations.

ORGANISM(S): Homo sapiens

PROVIDER: GSE154559 | GEO | 2020/12/10

REPOSITORIES: GEO

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NFATC2 modulates radiation toxicity in dermal fibroblasts from patients with severe side-effects of radiotherapy

Project description:NFATC2 modulates radiation toxicity in dermal fibroblasts from patients with severe side-effects of radiotherapy

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A radiation-induced gene expression signature as a tool to predict acute radiotherapy-induced adverse side effects

Project description:The majority of patients tolerate radiotherapy well, but some of them suffer from severe side effects. To find genes possibly predictive for radiosensitivity, mRNA profiles were generated before and 6 h after in vitro irradiation with 5 Gy. We analyzed lymphocytes from four head and neck and eight breast cancer patients with strong acute radiation toxicity and from 12 matching normal reacting patients in a blind study. In peripheral blood lymphocytes of all patients, 153 genes were identified which were statistically significantly altered by a fold change of more than 50% by irradiation. Pathway analysis revealed genes involved in p53 signalling, cell cycle control and apoptosis in response to radiation in primary lymphocytes. In these cells, a set of 67 radiation-induced genes was identified capable of differentiating between severe radiosensitive and normal reacting patients. More than one third of such classifying genes belong to the group of apoptosis or cell cycle regulating genes. Total RNA obtained from lymphocytes of cancer patients with strong acute radiation toxicity and from matching normal reacting patients were compared 6 hours after in vitro irradiation with 5 Gy.

2012-09-06 | E-GEOD-40640 | biostudies-arrayexpress

A radiation-induced gene expression signature as a tool to predict acute radiotherapy-induced adverse side effects

2012-09-06 | GSE40640 | GEO

Inefficient DNA-DSB repair via the homologous recombination pathway in prostate cancer patients with late radiation toxicity

Project description:Purpose: Severe late normal tissue damage limits radiotherapy treatment regimens. This study aims to validate γ-H2AX foci decay ratios and induced expression levels of DNA double strand break (DSB) repair genes, found in a retrospective study, as possible predictors for late radiation toxicity. Methods and Materials: Prospectively, decay ratios (initial/residual γ-H2AX foci numbers) and genome-wide expression profiles were examined in ex vivo irradiated lymphocytes of 198 prostate cancer patients. All patients were followed ≥2 years after radiotherapy, clinical characteristics were assembled and toxicity was recorded using the Common Terminology Criteria (CTCAE) v4.0. Results: No clinical factors were correlated with late radiation toxicity. Analysis of γ-H2AX foci uncovered a negative correlation between the foci decay ratio and toxicity grade. Significantly smaller decay ratios were found in grade≥3 compared to grade 0 patients (p=0.02), indicating less efficient DNA-DSB repair in radio-sensitive patients. Moreover, utilizing a foci decay ratio threshold determined in our previous retrospective study correctly classified 23 of the 28 grade≥3 patients (sensitivity, 82%) and 9 of the 14 grade 0 patients (specificity, 64%). Grade of toxicity also correlated with a reduced induction of the homologous recombination (HR) repair gene-set. The difference in average fold induction of the HR gene-set was most pronounced between grade 0 and grade≥3 patients (p=0.008). Conclusions: Reduced responsiveness of HR repair genes to irradiation and inefficient DSB repair correlate with an increased risk of late radiation toxicity. Using a decay ratio classifier, we could correctly classify 82% of the patients with grade≥3 toxicity. Additional studies are required to further optimize and validate the foci decay assay and to assess its predictive value for late radiation toxicity in patients prostate cancer

2017-01-30 | GSE85570 | GEO

A truncated MRE11 form induced by SPRTN is deficient in DNA repair and radiosensitises cancer cells

Project description:he human MRE11/RAD50/NBS1 (MRN) complex plays a crucial role in sensing and repairing DNA DSB. MRE11 possesses 3’-5’ exonuclease and endonuclease activity and forms the core of the multifunctional MRN complex. We previously identified a C-terminally truncated form of MRE11 (TR-MRE11) associated with post-translational MRE11 degradation. Here we identified the approximate cleavage site of TR-MRE11 at 559-580 amino acids, its DNA damage repair function and the factors regulating TR-MRE11 accumulation. The nuclease enzymatic activity of TR-MRE11 was dramatically reduced, associated with a lack of DNA binding efficiency, whilst TR-MRE11 still interacted efficiently with RAD50 and NBS1. Lack of the MRE11 C-terminal resulted in deficient HR repair and increased cellular radiosensitivity. Knockdown of SprT-like N-terminal domain (SPRTN), an essential metalloprotease for DNA-protein crosslink repair, resulted in failure of MRE11 cleavage, with TR-MRE11 protein levels being positively correlated with SPRTN protein expression. The presence of this DNA repair-defective C-terminal truncation could explain the finding of high MRE11 expression, by immunohistochemistry using an antibody against MRE11 prior to the C-terminal, being associated with survival following radical radiotherapy in cancer patients. Ultimately, understanding the functional differences between intact and repair-defective MRE11 may lead to improvements in patient outcomes through a more informed choice of treatment.

2021-02-23 | PXD017964 | Pride

Serum miRNA expression profile of nasopharyngeal carcinoma with different radiosensitivity

Project description:Nasopharyngeal carcinoma is a squamous cell carcinoma arising from the nasopharynx epithelium. So far, there have been no effective biomarkers to predict the radiosensitivity of NPC. Based on miRNA profile screened out from NPC patients with different radiosensitivity, this study was conducted to explore the correlation between serum miRNAs and radiotherapy response in NPC, and to identify biomarkers for predicting the radiosensitivity of NPC.

2020-03-30 | GSE139164 | GEO

Multi-Dimensional Epigenetic Analysis Reveals Transcription as a Primary Driver of Radiation Induced Double Strand Break Recognition

Project description:DNA Double Strand Breaks (DSBs) are a deleterious product of genotoxic agents or radiotherapy. Despite the inherent chromatin localization of DSBs, the literature has largely ignored the effect of local chromatin or histone post translational modifications (PTMs) on DSB induction or recognition especially in a therapy-relevant setting. Analysis of epigenetic linkages to the DNA Damage Response are challenging owing to the random nature of exogenous DSB induction. Here, we directly measure stochastic DNA damage induced by ionizing radiation (IR) and infer relationships between basal epigenetic states and cellular ability to detect DSBs. Contrary to the expected uniform localization of DSBs and γH2AX, we show that DSB recognition is separate from DSB induction and that both processes are dependent on the local chromatin milieu. In general, actively transcribed regions contain more γH2AX than heterochromatic regions suggesting a link between transcription and the DDR. In contrast to previous studies, we suggest that transcription proximal to DNA damage is necessary for early DSB detection and suggest a requirement for transcription mediated repair in genome maintenance. Finally, we reveal a dual effect of the repressive mark H3K27me3 on the DNA damage response. While basal H3K27me3 attenuates γH2AX deposition, transcribed regions recruit H3K27me3 following DSB induction possibly as an obligate step in DSB recognition. We uncover epigenetic determinants of DSB recognition and suggest new mechanisms by which the epigenome direct DNA repair. Our findings suggest new targets for radio-adjuvant therapy and reframe the current stochastic model of radiotherapy induced damage.

2021-12-31 | GSE181934 | GEO

Copy Number Variation data from non-trasformed human fibroblasts

Project description:The search for biomarkers to predict radiosensitivity is important not only to individualize radiotherapy of cancer patients but also to forecast radiation exposure risks. The aim of this study was to devise a machine learning method to stratify radiosensitivity and to investigate its association with copy number variations (CNVs) as markers of sensitivity to ionizing radiation. We used the Affymetrix CytoScan HD microarrays to for CNV estimation. Celluar radiosensitivity was measured by the clonogenic surviving fraction at 2 Gy (SF2).

2023-05-08 | GSE231621 | GEO

PDHE1α, PARylation, Acetyl-CoA, Acetylation, Histones, DNA damage repair

Project description:Chromatin relaxation is a prerequisite step that allows the DNA repair machinery to access double-strand breaks (DSBs), and local histones around the DNA breaks suffer from prompt acetylation changes. However, an intriguing question remains as to where the large demands of acetyl-CoA is precisely produced promptly. Here, we report that pyruvate dehydrogenase 1α (PDHE1α) catalyzes pyruvate metabolism to provide acetyl-CoA promptly in response to DNA damage. PDHE1α was quickly recruited to chromatin in a PARylation-dependent manner, which further drove acetyl-CoA generation to support local chromatin acetylation around the DSB regions. In turn, this process increased the formation of relaxed chromatin to benefit repair factor loading, thus promoting DSB repair to ultimately maintain genome stability and contribute to the resistance of cancer cells to DNA-damaging treatments in vitro and in vivo. In accordance with this, blocking PARylation-based PDHE1α chromatin recruitment markedly attenuated chromatin relaxation and the DSB repair efficiency, resulting in genome instability and restoration of radiosensitivity. Collectively, these findings reveal an undescribed mechanism that underlies site-directed acetyl-CoA generation involving chromatin-associated PDHE1α and its instrumental function in DNA repair and regulating local chromatin acetylation around DSB sites.

2023-07-27 | PXD040676 | Pride

The DNA Double-Strand Break Response Is Abnormal in Myeloblasts From Patients With Therapy-Related Acute Myeloid Leukemia

Project description:In order to examine if the upregulation of DNA repair genes on chromosome 8 was associated with the abnormal DSB phenotype observed in trisomy 8 (defined by array CGH or cytogenetics), we compared the mRNA levels of DNA repair genes on chromosome 8 in trisomy 8 t-AML patients versus normal t-AML gammaH2AX responders using gene expression array data. Bone marrow cells taken directly from patients after written informed consent were cryopreserved, RNA extracted, and microarray analysis was performed using Affymetrix U133plus2 chips.

2013-11-19 | E-GEOD-52478 | biostudies-arrayexpress

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