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1.
Cells ; 12(13)2023 06 29.
Artigo em Inglês | MEDLINE | ID: mdl-37443782

RESUMO

Alzheimer's disease (AD) is the most common neurodegenerative dementia, for which the molecular origins, genetic predisposition and therapeutic approach are still debated. In the 1980s, cells from AD patients were reported to be sensitive to ionizing radiation. In order to examine the molecular basis of this radiosensitivity, the ATM-dependent DNA double-strand breaks (DSB) signaling and repair were investigated by applying an approach based on the radiation-induced ataxia telangiectasia-mutated (ATM) protein nucleoshuttling (RIANS) model. Early after irradiation, all ten AD fibroblast cell lines tested showed impaired DSB recognition and delayed RIANS. AD fibroblasts specifically showed spontaneous perinuclear localization of phosphorylated ATM (pATM) forms. To our knowledge, such observation has never been reported before, and by considering the role of the ATM kinase in the stress response, it may introduce a novel interpretation of accelerated aging. Our data and a mathematical approach through a brand-new model suggest that, in response to a progressive and cumulative stress, cytoplasmic ATM monomers phosphorylate the APOE protein (pAPOE) close to the nuclear membrane and aggregate around the nucleus, preventing their entry in the nucleus and thus the recognition and repair of spontaneous DSB, which contributes to the aging process. Our findings suggest that pATM and/or pAPOE may serve as biomarkers for an early reliable diagnosis of AD on any fibroblast sample.


Assuntos
Doença de Alzheimer , Reparo do DNA , Humanos , Proteínas Mutadas de Ataxia Telangiectasia/metabolismo , Quebras de DNA de Cadeia Dupla , Doença de Alzheimer/diagnóstico , Doença de Alzheimer/metabolismo , Núcleo Celular/metabolismo
2.
Cancers (Basel) ; 14(24)2022 Dec 13.
Artigo em Inglês | MEDLINE | ID: mdl-36551628

RESUMO

There are a number of genetic syndromes associated with both high cancer risk and clinical radiosensitivity. However, the link between these two notions remains unknown. Particularly, some cancer syndromes are caused by mutations in genes involved in DNA damage signaling and repair. How are the DNA sequence errors propagated and amplified to cause cell transformation? Conversely, some cancer syndromes are caused by mutations in genes involved in cell cycle checkpoint control. How is misrepaired DNA damage produced? Lastly, certain genes, considered as tumor suppressors, are not involved in DNA damage signaling and repair or in cell cycle checkpoint control. The mechanistic model based on radiation-induced nucleoshuttling of the ATM kinase (RIANS), a major actor of the response to ionizing radiation, may help in providing a unified explanation of the link between cancer proneness and radiosensitivity. In the frame of this model, a given protein may ensure its own specific function but may also play additional biological role(s) as an ATM phosphorylation substrate in cytoplasm. It appears that the mutated proteins that cause the major cancer and radiosensitivity syndromes are all ATM phosphorylation substrates, and they generally localize in the cytoplasm when mutated. The relevance of the RIANS model is discussed by considering different categories of the cancer syndromes.

3.
Int J Mol Sci ; 23(18)2022 Sep 09.
Artigo em Inglês | MEDLINE | ID: mdl-36142346

RESUMO

Tissue overreactions (OR), whether called adverse effects, radiotoxicity, or radiosensitivity reactions, may occur during or after anti-cancer radiotherapy (RT). They represent a medical, economic, and societal issue and raise the question of individual response to radiation. To predict and prevent them are among the major tasks of radiobiologists. To this aim, radiobiologists have developed a number of predictive assays involving different cellular models and endpoints. To date, while no consensus has been reached to consider one assay as the best predictor of the OR occurrence and severity, radiation oncologists have proposed consensual scales to quantify OR in six different grades of severity, whatever the organ/tissue concerned and their early/late features. This is notably the case with the Common Terminology Criteria for Adverse Events (CTCAE). Few radiobiological studies have used the CTCAE scale as a clinical endpoint to evaluate the statistical robustness of the molecular and cellular predictive assays in the largest range of human radiosensitivity. Here, by using 200 untransformed skin fibroblast cell lines derived from RT-treated cancer patients eliciting OR in the six CTCAE grades range, correlations between CTCAE grades and the major molecular and cellular endpoints proposed to predict OR (namely, cell survival at 2 Gy (SF2), yields of micronuclei, recognized and unrepaired DSBs assessed by immunofluorescence with γH2AX and pATM markers) were examined. To our knowledge, this was the first time that the major radiosensitivity endpoints were compared together with the same cohort and irradiation conditions. Both SF2 and the maximal number of pATM foci reached after 2 Gy appear to be the best predictors of the OR, whatever the CTCAE grades range. All these major radiosensitivity endpoints are mathematically linked in a single mechanistic model of individual response to radiation in which the ATM kinase plays a major role.


Assuntos
Proteínas Quinases , Tolerância a Radiação , Proteínas Mutadas de Ataxia Telangiectasia/metabolismo , Biomarcadores/metabolismo , Sobrevivência Celular/efeitos da radiação , Reparo do DNA , Fibroblastos/metabolismo , Humanos , Proteínas Quinases/metabolismo , Tolerância a Radiação/efeitos da radiação
4.
Int J Mol Sci ; 23(3)2022 Jan 29.
Artigo em Inglês | MEDLINE | ID: mdl-35163494

RESUMO

Usher syndrome (USH) is a rare autosomal recessive disease characterized by the combination of hearing loss, visual impairment due to retinitis pigmentosa, and in some cases vestibular dysfunctions. Studies published in the 1980s reported that USH is associated with cellular radiosensitivity. However, the molecular basis of this particular phenotype has not yet been documented. The aim of this study was therefore to document the radiosensitivity of USH1-a subset of USH-by examining the radiation-induced nucleo-shuttling of ATM (RIANS), as well as the functionality of the repair and signaling pathways of the DNA double-strand breaks (DSBs) in three skin fibroblasts derived from USH1 patients. The clonogenic cell survival, the micronuclei, the nuclear foci formed by the phosphorylated forms of the X variant of the H2A histone (É£H2AX), the phosphorylated forms of the ATM protein (pATM), and the meiotic recombination 11 nuclease (MRE11) were used as cellular and molecular endpoints. The interaction between the ATM and USH1 proteins was also examined by proximity ligation assay. The results showed that USH1 fibroblasts were associated with moderate but significant radiosensitivity, high yield of micronuclei, and impaired DSB recognition but normal DSB repair, likely caused by a delayed RIANS, suggesting a possible sequestration of ATM by some USH1 proteins overexpressed in the cytoplasm. To our knowledge, this report is the first radiobiological characterization of cells from USH1 patients at both molecular and cellular scales.


Assuntos
Proteínas Mutadas de Ataxia Telangiectasia/metabolismo , Tolerância a Radiação/genética , Síndromes de Usher/enzimologia , Síndromes de Usher/genética , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos da radiação , Células Clonais , Difosfonatos/farmacologia , Fibroblastos/efeitos dos fármacos , Fibroblastos/patologia , Fibroblastos/efeitos da radiação , Histonas/metabolismo , Humanos , Cinética , Proteína Homóloga a MRE11/metabolismo , Micronúcleos com Defeito Cromossômico/efeitos da radiação , Modelos Biológicos , Fosforilação/efeitos dos fármacos , Fosforilação/efeitos da radiação , Tolerância a Radiação/efeitos dos fármacos , Tolerância a Radiação/efeitos da radiação , Frações Subcelulares/efeitos dos fármacos , Frações Subcelulares/metabolismo , Frações Subcelulares/efeitos da radiação
5.
Nat Commun ; 13(1): 173, 2022 01 10.
Artigo em Inglês | MEDLINE | ID: mdl-35013311

RESUMO

Mechanisms of drug-tolerance remain poorly understood and have been linked to genomic but also to non-genomic processes. 5-fluorouracil (5-FU), the most widely used chemotherapy in oncology is associated with resistance. While prescribed as an inhibitor of DNA replication, 5-FU alters all RNA pathways. Here, we show that 5-FU treatment leads to the production of fluorinated ribosomes exhibiting altered translational activities. 5-FU is incorporated into ribosomal RNAs of mature ribosomes in cancer cell lines, colorectal xenografts, and human tumors. Fluorinated ribosomes appear to be functional, yet, they display a selective translational activity towards mRNAs depending on the nature of their 5'-untranslated region. As a result, we find that sustained translation of IGF-1R mRNA, which encodes one of the most potent cell survival effectors, promotes the survival of 5-FU-treated colorectal cancer cells. Altogether, our results demonstrate that "man-made" fluorinated ribosomes favor the drug-tolerant cellular phenotype by promoting translation of survival genes.


Assuntos
Antimetabólitos Antineoplásicos/farmacologia , Neoplasias Colorretais/tratamento farmacológico , DNA de Neoplasias/genética , Tolerância a Medicamentos/genética , Fluoruracila/farmacologia , Biossíntese de Proteínas/efeitos dos fármacos , Receptor IGF Tipo 1/genética , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Neoplasias Colorretais/genética , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/patologia , Replicação do DNA , DNA de Neoplasias/metabolismo , Resistencia a Medicamentos Antineoplásicos/genética , Células HCT116 , Halogenação , Humanos , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , RNA Ribossômico/genética , RNA Ribossômico/metabolismo , Receptor IGF Tipo 1/agonistas , Receptor IGF Tipo 1/metabolismo , Ribossomos/efeitos dos fármacos , Ribossomos/genética , Ribossomos/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
6.
Biomolecules ; 11(10)2021 10 05.
Artigo em Inglês | MEDLINE | ID: mdl-34680095

RESUMO

Despite a considerable amount of data, the molecular and cellular bases of the toxicity due to metal exposure remain unknown. Recent mechanistic models from radiobiology have emerged, pointing out that the radiation-induced nucleo-shuttling of the ATM protein (RIANS) initiates the recognition and the repair of DNA double-strand breaks (DSB) and the final response to genotoxic stress. In order to document the role of ATM-dependent DSB repair and signalling after metal exposure, we applied twelve different metal species representing nine elements (Al, Cu, Zn Ni, Pd, Cd, Pb, Cr, and Fe) to human skin, mammary, and brain cells. Our findings suggest that metals may directly or indirectly induce DSB at a rate that depends on the metal properties and concentration, and tissue type. At specific metal concentration ranges, the nucleo-shuttling of ATM can be delayed which impairs DSB recognition and repair and contributes to toxicity and carcinogenicity. Interestingly, as observed after low doses of ionizing radiation, some phenomena equivalent to the biological response observed at high metal concentrations may occur at lower concentrations. A general mechanistic model of the biological response to metal exposure based on the nucleo-shuttling of ATM is proposed to describe the metal-induced stress response and to define quantitative endpoints for toxicity and carcinogenicity.


Assuntos
Proteínas Mutadas de Ataxia Telangiectasia/química , Quebras de DNA de Cadeia Dupla/efeitos dos fármacos , Reparo do DNA/efeitos dos fármacos , Metais/química , Alumínio/farmacologia , Proteínas Mutadas de Ataxia Telangiectasia/efeitos dos fármacos , Proteínas Mutadas de Ataxia Telangiectasia/efeitos da radiação , Cádmio/farmacologia , Cromo/farmacologia , Cobre/farmacologia , Reparo do DNA/efeitos da radiação , Humanos , Ferro/farmacologia , Chumbo/farmacologia , Metais/farmacologia , Metais/toxicidade , Níquel/farmacologia , Paládio/farmacologia , Zinco/farmacologia
7.
Int J Mol Sci ; 22(13)2021 Jul 02.
Artigo em Inglês | MEDLINE | ID: mdl-34281212

RESUMO

The individual response to ionizing radiation (IR) raises a number of medical, scientific, and societal issues. While the term "radiosensitivity" was used by the pioneers at the beginning of the 20st century to describe only the radiation-induced adverse tissue reactions related to cell death, a confusion emerged in the literature from the 1930s, as "radiosensitivity" was indifferently used to describe the toxic, cancerous, or aging effect of IR. In parallel, the predisposition to radiation-induced adverse tissue reactions (radiosensitivity), notably observed after radiotherapy appears to be caused by different mechanisms than those linked to predisposition to radiation-induced cancer (radiosusceptibility). This review aims to document these differences in order to better estimate the different radiation-induced risks. It reveals that there are very few syndromes associated with the loss of biological functions involved directly in DNA damage recognition and repair as their role is absolutely necessary for cell viability. By contrast, some cytoplasmic proteins whose functions are independent of genome surveillance may also act as phosphorylation substrates of the ATM protein to regulate the molecular response to IR. The role of the ATM protein may help classify the genetic syndromes associated with radiosensitivity and/or radiosusceptibility.


Assuntos
Neoplasias Induzidas por Radiação/etiologia , Tolerância a Radiação , Suscetibilidade a Doenças , Humanos
8.
Int J Radiat Biol ; 97(3): 317-328, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33320757

RESUMO

PURPOSE: MacCune-Albright syndrome (MAS) is a rare autosomal dominant osteo-hormonal disorder. MAS is characterized by a severe form of polyostotic fibrous dysplasia, 'café-au-lait' pigmentation of the skin and multiple endocrinopathies. MAS was shown to be caused by mosaic missense somatic mutations in the GNAS gene coding for the alpha-subunit of the stimulatory G-protein. MAS is also associated with radiation-induced malignant tumors, like osteosarcoma, fibrosarcoma and chondrosarcoma but their origin remains misunderstood. In parallel, bisphosphonates treatment was shown to improve the MAS patients' outcome, notably by increasing bone density but, again, the molecular mechanisms supporting these observations remain misunderstood. MATERIALS AND METHODS: Here, by using fibroblast and osteoblast cell lines derived from 2 MAS patients, the major radiobiological features of MAS were investigated. Notably, the clonogenic cell survival, the micronuclei and the γH2AX, pATM and MRE11 immunofluorescence assays were applied to MAS cells. RESULTS: It appears that cells from the 2 MAS patients are associated with a moderate but significant radiosensitivity, a delayed radiation-induced nucleoshuttling of the ATM kinase likely caused by its sequestration in cytoplasm, suggesting impaired DNA double-strand breaks (DSB) repair and signaling in both fibroblasts and osteoblasts. Such delay may be partially corrected by using bisphosphonates combined with statins, which renders cells more radioresistant. CONCLUSIONS: Our findings represent the first radiobiological characterization of fibroblasts and osteoblasts providing from MAS patients. Although the number of studied cases is reduced, our findings suggest that the MAS cells tested belong to the group of syndromes associated with moderate but significant radiosensitivity. Further investigations are however required to secure the clinical transfer of the combination of bisphosphonates and statins, to reduce the disease progression and to better evaluate the potential risks linked to radiation exposure.


Assuntos
Proteínas Mutadas de Ataxia Telangiectasia/fisiologia , Difosfonatos/administração & dosagem , Displasia Fibrosa Poliostótica/tratamento farmacológico , Inibidores de Hidroximetilglutaril-CoA Redutases/administração & dosagem , Tolerância a Radiação , Adulto , Linhagem Celular , Reparo do DNA , Feminino , Fibroblastos/efeitos da radiação , Displasia Fibrosa Poliostótica/genética , Humanos , Proteína Homóloga a MRE11/análise , Masculino , Osteoblastos/efeitos da radiação
9.
Curr Eye Res ; 46(4): 546-557, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-32862699

RESUMO

PURPOSE/AIM OF THE STUDY: Retinoblastoma (Rb) is a rare form of pediatric cancer that develops from retina cells. Bilateral and some unilateral forms of Rb are associated with heterozygous germline mutations of the (retinoblastoma 1) RB1 gene. RB1 mutations are also associated with a significant risk of secondary malignancy like head and neck tumors. Hence, to date, even if Rb patients are less subjected to radiotherapy to treat their primary ocular tumors, their healthy tissues may be exposed to significant doses of ionizing radiation during the treatment against their secondary malignancies with a significant risk of adverse tissue reactions (radiosensitivity) and/or radiation-induced cancer (radiosusceptibility). However, the biological role of the Rb protein in response to radiation remains misunderstood. Since the ataxia telangiectasia mutated (ATM) protein is a key protein of radiation response and since untransformed skin fibroblasts are a current model to quantify cellular radiosensitivity, we investigated here for the first time the functionality of the ATM-dependent signaling and repair pathway of the radiation-induced DNA double-strand breaks (DSB) in irradiated skin fibroblasts derived from Rb patients. MATERIALS AND METHODS: The major biomarkers of the DSB repair and signaling, namely clonogenic cell survival, micronuclei, nuclear foci of the phosphorylated forms of the X variant of the H2A histone (γH2AX), the phosphorylated forms of the ATM protein (pATM) and the meiotic recombination 11 nuclease (MRE11) were assessed in untransformed skin fibroblasts derived from three Rb patients. RESULTS: Skin fibroblasts from Rb patients showed significant cellular radiosensitivity, incomplete DSB recognition, delay in the ATM nucleo-shuttling and exacerbated MRE11 nuclease activity. Treatment with statin and bisphosphonates led to significant complementation of these impairments. CONCLUSIONS: Our findings strongly suggest the involvement of the ATM kinase in the radiosensitivity/radiosusceptibility phenotype observed in Rb cases.


Assuntos
Proteínas Mutadas de Ataxia Telangiectasia/metabolismo , Fibroblastos/efeitos da radiação , Tolerância a Radiação/fisiologia , Neoplasias da Retina/patologia , Retinoblastoma/patologia , Pele/efeitos da radiação , Anticolesterolemiantes/uso terapêutico , Conservadores da Densidade Óssea/uso terapêutico , Linhagem Celular , Quebras de DNA de Cadeia Dupla , Reparo do DNA , Combinação de Medicamentos , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Humanos , Pravastatina/uso terapêutico , Doses de Radiação , Proteínas de Ligação a Retinoblastoma/metabolismo , Pele/efeitos dos fármacos , Pele/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Raios X , Ácido Zoledrônico/uso terapêutico
10.
Dose Response ; 18(2): 1559325820913784, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32425719

RESUMO

Hormesis is a low-dose phenomenon that has been reported to occur, to different extents, in animals, plants, and microorganisms. However, a review of the literature shows that only a few reports describe it in humans. Also, the diversity of experimental protocols and cellular models used makes deciphering the mechanisms of hormesis difficult. In humans, hormesis mostly appears in the 20 to 75 mGy dose range and in nontransformed, radioresistant cells. In a previous paper by Devic et al, a biological interpretation of the adaptive response (AR) phenomenon was proposed using our model that is based on the radiation-induced nucleoshuttling of the ATM protein (the RIANS model). Here, we showed that the 20 to 75 mGy dose range corresponds to a maximum amount of ATM monomers diffusing into the nucleus, while no DNA double-strand breaks is produced by radiation. These ATM monomers are suggested to help in recognizing and repairing spontaneous DNA breaks accumulated in cells and contribute to reductions in genomic instability and aging. The RIANS model also permitted the biological interpretation of hypersensitivity to low doses (HRS)-another low-dose phenomenon. Hence, for the first time to our knowledge, hormesis, AR, and HRS can be explained using the same unified molecular model.

11.
Cells ; 9(4)2020 04 10.
Artigo em Inglês | MEDLINE | ID: mdl-32290274

RESUMO

BRCA1 inactivation is a hallmark of familial breast cancer, often associated with aggressive triple negative breast cancers. BRCA1 is a tumor suppressor with known functions in DNA repair, transcription regulation, cell cycle control, and apoptosis. In the present study, we demonstrate that BRCA1 is also a translational regulator. We previously showed that BRCA1 was implicated in translation regulation. Here, we asked whether translational control could be a novel function of BRCA1 that contributes to its tumor suppressive activity. A combination of RNA-binding protein immunoprecipitation, microarray analysis, and polysome profiling, was used to identify the mRNAs that were specifically deregulated under BRCA1 deficiency. Western blot analysis allowed us to confirm at the protein level the deregulated translation of a subset of mRNAs. A unique and dedicated cohort of patients with documented germ-line BRCA1 pathogenic variant statues was set up, and tissue microarrays with the biopsies of these patients were constructed and analyzed by immunohistochemistry for their content in each candidate protein. Here, we show that BRCA1 translationally regulates a subset of mRNAs with which it associates. These mRNAs code for proteins involved in major programs in cancer. Accordingly, the level of these key proteins is correlated with BRCA1 status in breast cancer cell lines and in patient breast tumors. ADAT2, one of these key proteins, is proposed as a predictive biomarker of efficacy of treatments recently recommended to patients with BRCA1 deficiency. This study proposes that translational control may represent a novel molecular mechanism with potential clinical impact through which BRCA1 is a tumor suppressor.


Assuntos
Proteína BRCA1/genética , Neoplasias de Mama Triplo Negativas/genética , Adulto , Idoso , Proteína BRCA1/metabolismo , Feminino , Genes Supressores de Tumor , Humanos , Pessoa de Meia-Idade , Transfecção , Neoplasias de Mama Triplo Negativas/metabolismo , Neoplasias de Mama Triplo Negativas/patologia
12.
Int J Radiat Biol ; 96(3): 394-410, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31738647

RESUMO

Purpose: Xeroderma Pigmentosum (XP) is a rare, recessive genetic disease associated with photosensitivity, skin cancer proneness, neurological abnormalities and impaired nucleotide excision repair of the UV-induced DNA damage. Less frequently, XP can be associated with sensitivity to ionizing radiation (IR). Here, a complete radiobiological characterization was performed on a panel of fibroblasts derived from XP-group D patients (XPD).Materials and methods: Cellular radiosensitivity and the functionality of the recognition and repair of chromosome breaks and DNA double-strand breaks (DSB) was evaluated by different techniques including clonogenic cell survival, micronuclei, premature chromosome condensation, pulsed-field gel electrophoresis, chromatin decondensation and immunofluorescence assays. Quantitative correlations between each endpoint were analyzed systematically.Results: Among the seven fibroblast cell lines tested, those derived from three non-relative patients holding the p.[Arg683Trp];[Arg616Pro] XPD mutations showed significant cellular radiosensitivity, high yield of residual micronuclei, incomplete DSB recognition, DSB and chromosome repair defects, impaired ATM, MRE11 relocalization, significant chromatin decondensation. Interestingly, XPD transduction and treatment with statins and bisphosphonates known to accelerate the radiation-induced ATM nucleoshuttling led to significant complementation of these impairments.Conclusions: Our findings suggest that some subsets of XPD patients may be at risk of radiosensitivity reactions and treatment with statins and bisphosphonates may be an interesting approach of radioprotection countermeasure. Different mechanistic models were discussed to better understand the potential specificity of the p.[Arg683Trp];[Arg616Pro] XPD mutations.


Assuntos
Transporte Ativo do Núcleo Celular , Proteínas Mutadas de Ataxia Telangiectasia/metabolismo , Mutação , Proteína Grupo D do Xeroderma Pigmentoso/genética , Xeroderma Pigmentoso/genética , Linhagem Celular , Sobrevivência Celular , Cromatina/metabolismo , Quebras de DNA de Cadeia Dupla , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Humanos , Proteína Homóloga a MRE11/metabolismo , Testes para Micronúcleos , Tolerância a Radiação , Radiação Ionizante , Raios Ultravioleta , Raios X
13.
Int J Mol Sci ; 20(21)2019 Oct 26.
Artigo em Inglês | MEDLINE | ID: mdl-31717816

RESUMO

Our understanding of the molecular and cellular response to ionizing radiation (IR) has progressed considerably. This is notably the case for the repair and signaling of DNA double-strand breaks (DSB) that, if unrepaired, can result in cell lethality, or if misrepaired, can cause cancer. However, through the different protocols, techniques, and cellular models used during the last four decades, the DSB repair kinetics and the relationship between cellular radiosensitivity and unrepaired DSB has varied drastically, moving from all-or-none phenomena to very complex mechanistic models. To date, personalized medicine has required a reliable evaluation of the IR-induced risks that have become a medical, scientific, and societal issue. However, the molecular bases of the individual response to IR are still unclear: there is a gap between the moderate radiosensitivity frequently observed in clinic but poorly investigated in the publications and the hyper-radiosensitivity of rare but well-characterized genetic diseases frequently cited in the mechanistic models. This paper makes a comprehensive review of semantic issues, correlations between cellular radiosensitivity and unrepaired DSB, shapes of DSB repair curves, and DSB repair biomarkers in order to propose a new vision of the individual response to IR that would be more coherent with clinical reality.


Assuntos
Quebras de DNA de Cadeia Dupla , Reparo do DNA/genética , Tolerância a Radiação/genética , Animais , Proteínas Mutadas de Ataxia Telangiectasia/genética , Proteínas Mutadas de Ataxia Telangiectasia/metabolismo , Biomarcadores/metabolismo , Citogenética/história , Reparo do DNA por Junção de Extremidades , Histonas/metabolismo , História do Século XX , História do Século XXI , Humanos , Radiação Ionizante , Pesquisa/história
14.
Cancers (Basel) ; 11(7)2019 Jun 28.
Artigo em Inglês | MEDLINE | ID: mdl-31261657

RESUMO

The evaluation of radiation-induced (RI) risks is of medical, scientific, and societal interest. However, despite considerable efforts, there is neither consensual mechanistic models nor predictive assays for describing the three major RI effects, namely radiosensitivity, radiosusceptibility, and radiodegeneration. Interestingly, the ataxia telangiectasia mutated (ATM) protein is a major stress response factor involved in the DNA repair and signaling that appears upstream most of pathways involved in the three precited RI effects. The rate of the RI ATM nucleoshuttling (RIANS) was shown to be a good predictor of radiosensitivity. In the frame of the RIANS model, irradiation triggers the monomerization of cytoplasmic ATM dimers, which allows ATM monomers to diffuse in nucleus. The nuclear ATM monomers phosphorylate the H2AX histones, which triggers the recognition of DNA double-strand breaks and their repair. The RIANS model has made it possible to define three subgroups of radiosensitivity and provided a relevant explanation for the radiosensitivity observed in syndromes caused by mutated cytoplasmic proteins. Interestingly, hyper-radiosensitivity to a low dose and adaptive response phenomena may be also explained by the RIANS model. In this review, the relevance of the RIANS model to describe several features of the individual response to radiation was discussed.

15.
Blood ; 130(14): 1628-1638, 2017 10 05.
Artigo em Inglês | MEDLINE | ID: mdl-28830887

RESUMO

Downregulation of CD20, a molecular target for monoclonal antibodies (mAbs), is a clinical problem leading to decreased efficacy of anti-CD20-based therapeutic regimens. The epigenetic modulation of CD20 coding gene (MS4A1) has been proposed as a mechanism for the reduced therapeutic efficacy of anti-CD20 antibodies and confirmed with nonselective histone deacetylase inhibitors (HDACis). Because the use of pan-HDACis is associated with substantial adverse effects, the identification of particular HDAC isoforms involved in CD20 regulation seems to be of paramount importance. In this study, we demonstrate for the first time the role of HDAC6 in the regulation of CD20 levels. We show that inhibition of HDAC6 activity significantly increases CD20 levels in established B-cell tumor cell lines and primary malignant cells. Using pharmacologic and genetic approaches, we confirm that HDAC6 inhibition augments in vitro efficacy of anti-CD20 mAbs and improves survival of mice treated with rituximab. Mechanistically, we demonstrate that HDAC6 influences synthesis of CD20 protein independently of the regulation of MS4A1 transcription. We further demonstrate that translation of CD20 mRNA is significantly enhanced after HDAC6 inhibition, as shown by the increase of CD20 mRNA within the polysomal fraction, indicating a new role of HDAC6 in the posttranscriptional mechanism of CD20 regulation. Collectively, our findings suggest HDAC6 inhibition is a rational therapeutic strategy to be implemented in combination therapies with anti-CD20 monoclonal antibodies and open up novel avenues for the clinical use of HDAC6 inhibitors.


Assuntos
Antígenos CD20/genética , Antineoplásicos/farmacologia , Inibidores de Histona Desacetilases/farmacologia , Histona Desacetilases/metabolismo , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Linfoma não Hodgkin/tratamento farmacológico , Rituximab/farmacologia , Animais , Antígenos CD20/imunologia , Linfócitos B/efeitos dos fármacos , Linfócitos B/imunologia , Linfócitos B/patologia , Linhagem Celular Tumoral , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Desacetilase 6 de Histona , Humanos , Leucemia Linfocítica Crônica de Células B/genética , Leucemia Linfocítica Crônica de Células B/imunologia , Leucemia Linfocítica Crônica de Células B/patologia , Linfoma não Hodgkin/genética , Linfoma não Hodgkin/imunologia , Linfoma não Hodgkin/patologia , Camundongos Endogâmicos BALB C , Camundongos SCID , RNA Mensageiro/genética , Células Tumorais Cultivadas , Regulação para Cima/efeitos dos fármacos
16.
Biochem J ; 473(7): 949-60, 2016 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-27026398

RESUMO

The tumour suppressor BRCA1 (breast and ovarian cancer-susceptibility gene 1) is implicated in several nuclear processes including DNA repair, transcription regulation and chromatin remodelling. BRCA1 also has some cytoplasmic functions including a pro-apoptotic activity. We identified ANKRD28 (ankyrin repeat domain 28) as a novel BRCA1-interacting protein in a yeast two-hybrid screen and confirmed this interaction by reciprocal immunoprecipitations of the two overexpressed proteins. Endogenous interaction between BRCA1 and ANKRD28 was also observed by co-immunoprecipitation and located in the cytoplasm by proximity ligation assay. The main site of interaction of ANKRD28 on BRCA1 is located in its intrinsically disordered scaffold central region. Whereas ANKRD28 silencing results in a destabilization of IκBε (inhibitor of nuclear factor κBε) through its activation of PP6 (protein phosphatase 6) co-regulator upon TNFα (tumour necrosis factor α) stimulation, BRCA1 overexpression stabilizes IκBε. A truncated form of BRCA1 that does not interact with ANKRD28 has no such effect. Our findings suggest that BRCA1 is a novel modulator of PP6 signalling via its interaction with ANKRD28. This new cytoplasmic process might participate in BRCA1 tumour-suppressor function.


Assuntos
Proteína BRCA1/metabolismo , Proteínas I-kappa B/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Fosfoproteínas Fosfatases/metabolismo , Proteínas Proto-Oncogênicas/metabolismo , Transdução de Sinais , Proteína BRCA1/genética , Feminino , Células HEK293 , Humanos , Proteínas I-kappa B/genética , Peptídeos e Proteínas de Sinalização Intracelular/genética , Células MCF-7 , Fosfoproteínas Fosfatases/genética , Proteínas Proto-Oncogênicas/genética , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismo
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