Dissertations / Theses on the topic 'SAMD14'
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Sébert, Marie. "Génétique et évolution clonale des syndromes d’insuffisance médullaire." Thesis, Sorbonne Paris Cité, 2018. http://www.theses.fr/2018USPCC271.
Full textInherited bone marrow failure (IBMF) syndromes are heterogeneous diseases related to germ line mutations causing deficient hematopoiesis in mutated patients. Mutations involve several families of genes with different biological pathways driving the bone marrow failure. Most germ line genetic BMF disorders are characterized by a high propensity to clonal evolution and to develop MDS or AML. We used a whole-exome sequencing (WES) comprehensive analysis on fibroblast DNA samples from 179 patients with BMF/MDS of unresolved inherited origin. We provided a molecular diagnosis for 86/179 BMF patients (48%) including several seldom-reported IBMF/MDS entities like SAMD9/SAMD9L, MECOM/EVI1, and ERCC6L2. In particular, we described a specific clonal evolution in patients having mutations in SAMD9 and SAMD9L.Fanconi anemia (FA) is the most common IBMF syndrome, caused by a germ line mutation in one gene of the FA pathway. DNA repair deficiency in patient’s FA cells leads to chromosomal instability, which sets the stage for clonal evolution with a specific pattern of chromosomal abnormalities. We used integrated clinical, next-generation genomic and functional studies on primary cells from a National cohort of 335 FA patients, including 98 with clonal evolution, to decipher the mechanisms of BM progression. While relatively few somatic point mutations were found, unbalanced translocations leading to gross chromosomal copy-number abnormalities were most prominent. Whole genome sequencing revealed an FA-specific signature in which microhomology-mediated end joining (MMEJ) or non homologous end joining (NHEJ) repair had mediated genome rearrangements, consistent with the constitutive homologous repair defect. Longitudinal studies confirmed the order of chromosomal events during FA patients oncogenesis: 1q+, 3q+, -7/del7q, del or RUNX1 mutations. A major initial step was duplication of chromosome 1q, resulting in strong expression of MDM4, a negative regulator of p53, which can be targeted by MDM4-inhibitors.IBMF are rare diseases and our study participated to describe new genetic and clinical entities. Studying the clonal evolution of IBMF syndromes can help to understand MDS and AML pathophysiology and lead to therapeutic target identification
Hani, Lylia. "Caractérisation et rôle des lymphocytes T CD4+ mémoires SAMHD1low au cours de l'infection par le VIH-1." Thesis, Paris Est, 2018. http://www.theses.fr/2018PESC0087/document.
Full textWe have previously reported the presence of memory CD4+ T cells that display low levels of SAMHD1 (SAMHD1low ) enriched in Th17 and Tfh cells. Here we investigated gene expression profile and the size and composition of HIV DNA population in SAMHD1 low cells.A total of 36 individuals on c-ART (median: 7y) with median CD4+ counts and nadir of 549 cells/ul and 210 cells/ul respectively, including 6 elite controllers (EC, CD4+: 900 cells/ul) and 8 healthy donors were studied. Blood memory CD4+ CD45RO+ SAMHD1low, CD45RO+ SAMHD1high and naive CD45RO- SAMHD1high cells were sorted. Cell associated HIV-1 DNA levels were quantified (HIV DNA Cell, Biocentric) and ultra-deep-sequencing (UDS, 454/Roche) of partial env (C2/V3) HIV-1 DNA was performed. Gene expression profile on sorted cells was deternined with RNA-Sequencing (Illumina RNASeq technology). Levels of HIV-1 DNA were significantly higher in memory SAMHD1low cells compared to SAMHD1high cells (4.5 [3.1-6.2] vs 3.8 [2.9-5.7] log/10 6 cells, respectively, p=0.02) among c-ART individuals, while naïve CD45RO- SAMHD1high showed lower levels (3.1 [1.6-4.4]). EC exhibited low HIV-1 DNA level in both SAMHD1low and SAMHD1high (1.6 and 2.3 log/10 6 cells respectively p>0.05). Naïve CD45RO - SAMHD1 high cells from EC showed lower DNA compared to naïve cells from c-ART pts (1.6 and 3.1 log/10 6 cells, respectively, p=0.01). Phylogenetic analyses revealed well-segregated HIV-DNA populations between subsets with significant compartmentalization between SAMHD1low and SAMHD1high cells in all but 2 participants (p<0.001) and limited viral exchange. Moreover SAMHD1low cells exhibited a distinct gene profile as compared to SAMHD1high allowing thus further characterisation of these cells.This pilot study revealed distinct HIV DNA populations in size and composition associated with unique genes profile in memory SAMHD1low cells. We show that memory SAMHD1low cells exhibit distinct genes profile which segregates them from the SAMHD1 high counterpart, and contain the highest level of HIV-1 DNA. We reveal distinct/well-segregated HIV-1 DNA populations in both subsets, suggesting minimal viral exchange
Argüelles, Camilla. "Étude du rôle de la protéine de liaison aux ARN messagers Smaug dans la voie Hedgehog chez la drosophile." Thesis, Sorbonne Paris Cité, 2017. http://www.theses.fr/2017USPCC053.
Full textHedgehog Proteins (HH) are major players of animal development and carcinogenesis. Their transduction requires the 7 transmembrane protein Smoothened (SMO) whose activity is regulated by Patched (PTC), the HH receptor and antagonist. PTC and HH regulates SMO trafficking, phosphorylation and accumulation but numerous aspects of these regulations remain poorly understood. During my thesis, I focused on Smaug, a new partner of SMO in drosophila which was identified in the laboratory in a yeast two-hybrid screen. Smaug is known to bind and repress numerous mRNA during embryonic development in fly. I analyzed how it acts on SMO and HH signaling and also how is it regulated by HH. I have shown that Smaug is a positive regulator of the HH pathway and that it probably acts via its capacity to bind mRNA. I have also demonstrated that SMO and Smaug colocalise in cytoplasmic foci in absence of signal and that SMO is sufficient to localized Smaug to the plasma membrane in response to HH. Finally, I highlighted an effect of SMO and HH on the phosphorylation of Smaug suggesting the existence of a regulatory loop
Valverde, Estrella Lorena. "TREX1 and SAMHD1, and Aicardi-Goutières Syndrome." Doctoral thesis, Universitat de Barcelona, 2015. http://hdl.handle.net/10803/291940.
Full textLa síndrome d'Aicardi-Goutières (AGS), és una malaltia autoimmunitària recessiva que mimetitza una infecció vírica intrauterina, i la qual és caracteritzada per calcificacions intracranials, atròfia cerebral i augment d'IFN-alfa al líquid cefaloraquidi. L'AGS és una malaltia genètica heterogènia associada amb mutacions al gen que codifica per a l'exonucleasa TREX1, a qualsevol dels gens codificants per a les components de la ribonucleasa RNASE H2, a la fosfohidrolasa SAMHD1, a la deaminasa ADAR1 o al sensor citoplasmàtic MDA5. El coneixement d'aquestes funcions és fonamental per tal d'entendre la patogènesi de l'AGS. En aquesta tesi s'ha aprofundit en el coneixement del mecanisme regulador de la transcripció de Samhd1. Hem vist que Samhd1 es troba expressat en diferents òrgans sense necessitat de cap estímul previ, com el pàncrees, l’intestí prim i els macròfags derivats de moll d’os, i en diferents quantitats en altres òrgans de ratolí. Donada la important afectació que té l’AGS al cervell, també es va analitzar la seva expressió en neurones i cèl·lules de la micròglia. També hem vist que Samhd1 es troba induït en presència de citocines proinflamatòries, però no es troba afectada la seva expressió en presència de citocines antiinflamatòries així com tampoc en presència de TNF-gamma. Utilitzant macròfags derivats de ratolins deficients en STAT1, hem pogut demostrar que l’expressió de Samhd1 per IFN-alfa és a través d’STAT1, ja que la seva expressió es troba completament reprimida en aquestes cèl·lules. Ens vam centrar en la inducció de Samhd1 i per la seva comprensió vam focalitzar en l’estudi del seu promotor. Es van clonar 1500 parells de bases del promotor de Samhd1 en un plasmidi reporter de luciferasa, i es va veure que aquest fragment era suficient per induir l’expressió de luciferasa. A partir d’aquest constructe, es van realitzar llavors noves construccions delecionant cada vegada una regió del promotor. Es va veure que en delecionar una regió específica de 161pb, l’expressió de luciferasa es trobava completament reprimida, indicant que aquesta regió del promotor és crítica per a la inducció de Samhd1. Experiments de retard en gel (EMSA) van mostrar que Samhd1 es troba reprimit en condicions basals per una proteïna que no hem arribat a caracteritzar, i experiments de precipitació de cromatina (ChIP) van mostrar que IRF1 es troba involucrada en la inducció de Samhd1 per IFN-alfa. La nostra hipòtesi doncs, és que l’expressió de Samhd1 té un mecanisme de regulació doble: en condicions basals es troba reprimit i en presència d’IFN-alfa s’indueix una via de senyalització independent d’STAT1 que fa saltar el complex repressor del promotor, i també s’indueix una via de senyalització dependent d’STAT1, que indueix l’expressió d’IRF1 i que activa la transducció de Samhd1. Fins ara no hem caracteritzat la proteïna o complex de proteïnes que reprimeix l’expressió de Samhd1 en condicions basals, però s’està investigant mitjançant anàlisis proteòmics. En aquesta tesi també s’ha fet la construcció d’un ratolí KO condicional per a TREX1. Una vegada aconseguit aquest animal condicional, el qual conté el gen de Trex1 flanquejat per dues dianes LoxP, aquest s’està encreuant amb diferents soques que expressen CRE sota regulació de diferents Socs2 promotors. Els ratolins homozigots KO i que expressen CRE, tenen un fenotip similar al fenotip que mostren els ratolins KO totals de TREX1. Estem en el procés d’obtenció de ratolins homozigots KO i que expressen CRELysM però, donat a problemes amb la penetrància d’aquest al·lel, hem tingut algunes dificultats. Els resultats d’aquesta tesi en conjunt poden ajudar a entendre una mica més el funcionament de l'AGS.
Antonucci, Jenna Marie. "Mechanisms of HIV-1 Restriction by the Host Protein SAMHD1." The Ohio State University, 2018. http://rave.ohiolink.edu/etdc/view?acc_num=osu1524006072232491.
Full textLouis, Tania. "Étude des fonctions cellulaires de SAMHD1, facteur de restriction du VIH-1." Thesis, Montpellier, 2015. http://www.theses.fr/2015MONTS050/document.
Full textUnderstanding host pathogen interactions reveals not only important information regarding the replication cycle of the pathogen but it often leads to the discovery and better understanding of key biological processes of the host. The aim of my PhD was to decipher the cellular functions of the HIV-1 restriction factor SAMHD1. SAMHD1 (SAM domain and HD domain-containing protein 1) is expressed in most human tissues. This protein is able to hydrolyze cellular deoxyribonucleotides triphosphate (dNTP) and possesses a nuclease activity primarily against single stranded RNA. Mutations in SAMHD1 have been described in patients suffering from an auto-immune disease causing premature death of newborns. This phenotype suggests a role of SAMHD1 in the control of immune response. Moreover, SAMHD1 restricts HIV-1 in non-cycling cells. The HIV-2 accessory protein Vpx induces SAMHD1 degradation by the proteasome, conferring cell permissiveness to HIV. In fact, the antiviral activity of SAMHD1 has been extended to other viruses including Herpes Simplex Virus 1 and Hepatitis B virus. Nevertheless, the mechanism by which SAMHD1 restrict HIV replication is debated. It was initially thought to act by depleting the dNTP pool but recent studies highlighted a potential role of SAMHD1 nuclease function in degrading HIV-1 genomic RNA. Many studies aiming at understanding the antiviral activity of SAMHD1 are being pursued, whereas little is known about the cellular function of this protein. The fact that SAMHD1 is able to regulate the cellular dNTP pool and to interact with nucleic acids suggests a key role of this protein in cellular processes, such as DNA replication and repair. During my PhD, I showed that SAMHD1 modulates the cell cycle, as the overexpression of this protein slows down cell proliferation. I also observed that SAMHD1 overexpression increases cellular sensitivity to double strand DNA breaks-inducing agents. Moreover I discovered that, after double strand breaks induction, SAMHD1 is specifically regulated by phosphorylation on its threonine 592 and recruited at the damaged sites. Other studies confirmed the importance of SAMHD1 regulation along the cell cycle as its overexpression and depletion both decrease cell proliferation. In addition to my observations, some studies suggested that SAMHD1 is important to maintain genomic integrity, presumably through its implication in DNA repair. Altogether, these results promote SAMHD1 as a key player in cellular homeostasis. I additionally showed that SAMHD1 expression is reduced in 80% of patients suffering from chronic lymphocytic leukemia (CLL). SAMHD1 loss is therefore correlated to the development of a disease due to disturbances of cellular integrity. Looking at samples from different types of tumors, I showed that SAMHD1 loss is shared between all tested cancers, although at lesser extent than in CLL. My PhD work underlines the central role of SAMHD1 to maintain cellular integrity
Jaffer, Ali Mohammed Hakim. "Multifaceted roles of the transmembrane nuclear envelope protein, Samp1." Doctoral thesis, Stockholms universitet, Institutionen för neurokemi, 2017. http://urn.kb.se/resolve?urn=urn:nbn:se:su:diva-141816.
Full textAt the time of the doctoral defense, the following papers were unpublished and had a status as follows: Paper 3: Manuscript. Paper 4: Manuscript. Paper 5: Manuscript.
Silva, Maria-João. "Role of CTF18 and SAMHD1 in human DNA replication and genome integrity maintenance." Thesis, Montpellier 2, 2014. http://www.theses.fr/2014MON20236.
Full textS phase is a critical period of the cell cycle during which the genome is particularly vulnerable. The efficient duplication of eukaryotic genomes depends on the unperturbed progression of thousands of replication forks.The early stages of tumorigenesis are associated with spontaneous replication stress, characterized with a blockage of fork progression. Understanding how replication stress arises in normal cells and contributes to tumorigenesis is a major challenge in cancer research.My thesis work aims at understanding the regulation of replication fork progression by two different proteins, SAMHD1 and CTF18, which have important roles in various aspects of DNA metabolism.Faithful duplication of the genome depends on a balanced supply of deoxyribonucleoside triphosphates (dNTPs). Imbalanced dNTP pools decrease the fidelity of DNA polymerases and increase mutation rates. SAMHD1 was originally identified as a dNTP triphosphohydrolase. This enzyme is implicated in Aicardi-Goutières syndrome. It has also been identified as a component of the human innate immune system that restricts HIV-1 infection. Recently, SAMHD1 was shown to be involved in the regulation of dNTP pools in cultured human cells. This protein is maximally expressed during quiescence and minimally during S phase. However, the impact of SAMHD1 upon DNA replication has not been addressed. Using DNA fiber spreading, we found that SAMHD1 modulates the speed of fork progression. In addition to its dNTPase activity, SAMHD1 contains a putative 3'-5' exonuclease domain that cleaves both DNA and RNA in vitro. A growing body of evidence indicates that 3'-5' exonucleases are critical to ensure fork progression and the fidelity of DNA replication. Remarkably, we found that the exonuclease activity of SAMHD1 promotes backtracking at paused forks and is important for replication fork progression. We propose that this backtracking activity is important to remove miss-incorporated deoxynucleotides or ribonucleotides. Our finding may have implications for our understanding of the link between SAMHD1 and the Aicardi-Goutières syndrome.CTF18 is part of a RFC-like complex involved in sister chromatid cohesion (SCC). In human cells it has been suggested that CTF18 controls the progression of replication forks, presumably by promoting acetylation of the SMC3 cohesin at replication forks. However, several results indicate that the function of CTF18 is not restricted to the establishment of SCC. Indeed, our group has shown that the yeast Ctf18 is essential for activation of the replication checkpoint, independently of its role in SCC. In human, CTF18 also participates in the recruitment of PCNA, the processivity factor of DNA polymerases δ and ε. CTF18 also interacts with the translesion polymerase . The aim of my work was to characterize the role of CTF18 during DNA replication. Using DNA combing, we first noticed that replication fork speed is slower in CTF18-depleted cells under unperturbed conditions. Intriguingly, increased fork speed was observed in CTF18-depleted cells challenged with hydroxyurea (HU), which is reminiscent of the phenotype of SAMHD1-depleted cells. Using iPOND, we observed an accumulation of PCNA at replication forks in HU-treated CTF18-depleted cells. We also found that CTF18 depletion induces an accumulation of yH2AX, suggesting that CTF18 is required for genome stability. Finally, we observed that the resection mediated by SAMHD1 at paused forks does not occur in the absence of CTF18. Together, these data indicate that CTF18 acts upstream of SAMHD1 at stalled forks, presumably through the unloading of PCNA
Qin, Zhihua. "SAMHD1 Negatively Regulates the Innate Immune Responses to Inflammatory Stimuli and Viral Infection." The Ohio State University, 2020. http://rave.ohiolink.edu/etdc/view?acc_num=osu1587587968104986.
Full textCenker, Jennifer Jean. "DIFFERENTIAL HIV-1 SUSCEPTIBILITY OF PRIMARY MACROPHAGE POPULATIONS." Case Western Reserve University School of Graduate Studies / OhioLINK, 2017. http://rave.ohiolink.edu/etdc/view?acc_num=case1491656059069304.
Full textWang, Feifei. "Comparison of Murine and Human SAMHD1’s Role in Retroviral Restriction and Cell Cycle Progression." The Ohio State University, 2015. http://rave.ohiolink.edu/etdc/view?acc_num=osu1448450028.
Full textMarc, Corral Juan. "Molecular genetics of autosomal dominant ataxias: identification and characterisation of two novel spinocerebellar ataxia subtypes." Doctoral thesis, Universitat Autònoma de Barcelona, 2021. http://hdl.handle.net/10803/672062.
Full textLas ataxias espinocerebelosas (SCAs) consisten en un grupo heterogéneo de trastornos del movimiento hereditarios caracterizados clínicamente por ataxia progresiva asociada de forma variable con otros signos neurológicos adicionales como signos piramidales o extrapiramidales, oftalmoplejía, retinosis pigmentaria, demencia o convulsiones. La heterogeneidad clínica se explica por la heterogeneidad genética, con más de 53 loci y 40 genes identificados asociados hasta la fecha. En esta tesis se ha estudiado una cohorte de 308 pacientes con ataxia, identificando variantes genéticas causativas en 82 casos índice (26,6%), 45 de ellas no descritas previamente. Durante el curso de esta tesis, nuestro grupo identificó un nuevo subtipo de ataxia, SCA37, y localizó su defecto genético en el cromosoma 1p32. En el presente estudio se ha identificado la mutación intrónica repetitiva e inestable ATTTC dentro de la región reguladora 5’ no codificante del gen Disabled 1 (DAB1) como el defecto genético causante de SCA37. Además, se describe la correlación clínico-genética y los primeros hallazgos neuropatológicos en SCA37 que indican que la enfermedad está causada por la desregulación de la expresión de DAB1 en el cerebelo con pérdida severa de células de Purkinje en la corteza cerebelosa y la presencia de gránulos perisomáticos ubiquitinados e inmunoteñidos para DAB1. Es importante destacar que la repetición ATTTC desregula la expresión del ARN de DAB1 resultando en la sobreexpresión de la ruta de señalización mediada por reelina-DAB1 y PI3K/AKT en el cerebelo SCA37. Por último, pero no menos importante, se han realizado estudios de ligamiento del genoma completo y secuenciación del exoma en una familia de Menorca con siete individuos afectos que presentaban ataxia, nistagmo, disartria, polineuropatía y signos piramidales de forma variable y con una herencia autosómica dominante. La edad de inicio de la enfermedad oscila entre los 15 y 50 años. Las resonancias magnéticas revelaron atrofia cerebelosa con desmielinización cerebral, y los estudios neurofisiológicos mostraron polineuropatía sensitiva axonal moderada con respuesta cutánea simpática anormal predominantemente en las extremidades inferiores. Se identificó la variante c.1877C> T (p.Ser626Leu) en el gen SAMD9L como el defecto genético causante de la enfermedad. El estudio también demuestra la localización mitocondrial de la proteína SAMD9L humana, con niveles disminuidos en fibroblastos de los pacientes, así como deficiencias mitocondriales y lisosomales en este nuevo subtipo de ataxia. Además, la sobreexpresión del ARNm de SAMD9L mutado humano demuestra deterioro de la movilidad y afectación vestibular/sensorial en los embriones del pez cebra. En conclusión, este estudio ha identificado los déficits genéticos en el 26,6% de nuestros casos de ataxia, demuestra la mutación intrónica repetitiva e inestable ATTTC dentro del gen DAB1 como la causa genética subyacente proporcionando evidencia de la desregulación de la señalización mediada por reelina-DAB1 en la ataxia espinocerebelosa tipo 37, y describe un nuevo subtipo de ataxia espinocerebelosa causada por la mutación SAMD9L, que desencadena una desregulación mitocondrial y lisosomal, apuntando al papel de SAMD9L en las funciones neurológicas motoras y sensoriales. Como resultado de esta tesis, se aportan nuevos conocimientos sobre los mecanismos clínicos, genéticos y fisiopatológicos subyacentes a la neurodegeneración en las ataxias espinocerebelosas, y se identifican nuevas dianas terapéuticas candidatas para el tratamiento.
Spinocerebellar ataxias (SCAs) consist of a heterogeneous group of inherited movement disorders clinically characterised by progressive ataxia variably associated with additional neurological signs such as pyramidal or extrapyramidal signs, ophthalmoplegia, pigmentary retinopathy, dementia or seizures. This clinical heterogeneity is explained by its genetic heterogeneity, with more than 53 loci and 40 genes identified and associated to date. In this thesis, a cohort of 308 ataxia patients were studied, finding causative genetic variants in 82 index cases (26.6%), 45 of them previously not described. During the course of this thesis our group identified a novel SCA37 ataxia subtype and localised its genetic defect to chromosome 1p32. The present study identifies the unstable intronic ATTTC repeat mutation within the 5′-non-coding regulatory region of the Disabled 1 gene (DAB1), as the causative genetic defect of SCA37. Moreover, it describes the clinical-genetic correlation and the first neuropathological findings in SCA37 which reveal that the disease is caused by dysregulation of cerebellar DAB1 expression with severe loss of Purkinje cells in the cerebellar cortex, and the presence of ubiquitinated perisomatic granules immunostained for DAB1. Importantly, the ATTTC repeat induced DAB1 RNA switch resulting in the upregulation of reelin-DAB1 and PI3K/AKT signalling in the SCA37 cerebellum. Last but not least, whole-genome linkage and exome studies were performed in a family from Menorca with seven affected individuals variably presenting with ataxia, nystagmus, dysarthria, polyneuropathy and pyramidal signs with an autosomal dominant inheritance. Variable age at onset ranged from 15 to 50 years. MRI revealed cerebellar atrophy with cerebral demyelination, and neurophysiological studies showed moderate axonal sensory polyneuropathy with abnormal sympathetic skin response predominantly in the lower limbs. The c.1877C>T (p.Ser626Leu) variant in the SAMD9L gene was identified as the disease causative genetic defect. The study also demonstrated the mitochondrial location of human SAMD9L protein, with its levels decreased in patients’ fibroblasts and evidenced mitochondrial and lysosomal deficits in this novel ataxia subtype. In addition, overexpression of the human mutated SAMD9L mRNA revealed impaired mobility and vestibular/sensory functions in zebrafish embryos. In conclusion, this study identifies the genetic deficits in 26.6% of our ataxia cases, demonstrates the unstable ATTTC repeat mutation within the DAB1 gene as the underlying genetic cause providing evidence of reelin-DAB1 signalling dysregulation in the spinocerebellar ataxia type 37, and describes a novel spinocerebellar ataxia subtype caused by SAMD9L mutation, which triggers mitochondrial and lysosomal dysregulation, pointing to the role of SAMD9L in neurological motor and sensory functions. As a result of this thesis novel insights into the clinical, genetic and physiopathological mechanisms underlying neurodegeneration in spinocerebellar ataxias are identified providing new candidate targets for treatment.
Universitat Autònoma de Barcelona. Programa de Doctorat en Neurociències
Pham, Thu Hang. "Molecular biology and biochemistry of the polyamine pathway in rice : the role of SAMDC." Thesis, University of Newcastle Upon Tyne, 2002. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.275414.
Full textCoquel, Flavie. "Etude du rôle de SAMHD1 dans la réponse au stress réplicatif et la production d’interférons de type I." Thesis, Montpellier, 2018. http://www.theses.fr/2018MONTT043/document.
Full textDNA replication is an utterly complex process, implicating thousands of replication forks that progress along chromosomes. These forks frequently slow-down or stall when they encounter obstacles such as DNA secondary structures, proteins acting on chromatin or a lack of dNTPs. Such impediment on the progression of replication forks, termed replication stress, plays a major role in tumorigenesis. Intricate processes, still not entirely understood, are established to respond to this stress. For instance, nucleases such as DNA2 and MRE11 degrade nascent DNA at arrested forks to allow their restart.The interferon pathway is a defense mechanism against pathogens that detects non-self-nucleic acids in the cytosol to activate the innate immune response. However, DNA fragments originating from the metabolism of genomic DNA, such as DNA repair and retrotransposition, may also diffuse into the cytosol to activate this pathway. The Aicardi-Goutières Syndrome (AGS), a rare genetic disorder characterized by neurological and developmental defects is caused by chronic inflammation due to the over-production of type I IFNs. It has been proposed that DNA replication may generate cytosolic DNA fragments triggering this encephalopathy. However, the mechanisms involved have remained unexplored.SAMHD1 is frequently mutated in the Aicardi-Goutières Syndrome as well as in some cancers. However, its role in the etiology of these diseases remains poorly understood. This HIV-1 restriction factor has a dNTPase activity involved in the regulation of dNTP pools and a putative 3’-5’ exonuclease activity.The goal of my PhD thesis was to understand the molecular mechanisms responsible for inflammation induced by SAMHD1 deficiency.We show that cytosolic DNA accumulates in SAMHD1-deficient cells, especially in conditions of replication stress, activating the interferon response. In addition, we demonstrate that SAMHD1 is necessary for DNA replication and for the processing of arrested forks, independently of its dNTPase activity. SAMHD1 stimulates the exonuclease activity of MRE11 in vitro. In the absence of SAMHD1, nascent DNA degradation is inhibited, preventing replication checkpoint activation and fork restart. Besides, forks are aberrantly processed by an alternative pathway that generates cytosolic DNA fragments, thereby activating the interferon response.Altogether, we demonstrate for the first time a direct link between the DNA replication stress response and interferon production. This result has important consequences regarding our understanding of the Aicardi-Goutières Syndrome and cancers caused by SAMHD1 mutations, which could be translated into new therapeutic opportunities. For instance, we have shown that MRE11 and RECQ1 are responsible for the production of DNA fragments triggering the pro-inflammatory response in SAMHD1-deficient cells. Inhibiting these enzymes decreases the production of cytosolic nucleic acids and, consequently, reduces the activation of cell-autonomous innate immunity in SAMHD1-depleted cells. Accordingly, inhibiting these enzymes may as well decrease IFN production in AGS in vivo models caused by SAMHD1 mutations. The interferon pathway also plays a major role in tumorigenesis as well as in the clinical efficacy of irradiation and some chemotherapeutic agents such as oxaliplatin. Modulating this response may therefore have much broader implications in anti-cancer therapy
Kung, Jason. "Effects of ionizing radiation on osseous healing in SAMR1 and SAMP6 mice: a histiological study." Thesis, Boston University, 2012. https://hdl.handle.net/2144/12460.
Full textPrevious studies have showed effects of irradiation on bone and on fracture healing. This is a histological study of the effect of a combined irradiation/fracture injury model in a strain of aged mice (SAMP6) and controls (SAMR1) and the effects of the radioprotective agent, JP4-039 (a mitochondria targeted GS-nitroxide). Hind legs in SAMR1 and SAMP6 control mice and mice pretreated with JP4-039 were exposed to a single dose of radiation (0 or 20 Gy). Twenty four hours after irradiation, unicortical osseous wounds were created in each proximal tibia. Mice were sacrificed at intervals (14, 21 days), tibias excised, radiographed, and prepared for histology (day 21 only). Tibias were examined and graded histologically for evidence of cortical bridging and intramedullary fibrosis. Irradiated SAMP6 wounds showed significantly diminished cortical bridging and significantly more intramedullary fibrosis. In contrast, JP4-039 showed a statistical trend in ameliorating intramedullary fibrosis in irradiated SAMP6 mice. In control SAMR1 mice, JP4-039 had no significant effect on cortical bridging or fibrosis with the number of replicates available. In summary, SAMP6 mice display diminished capacity to recover from the combined irradiation/fracture injury model, with subgroups pretreated with JP4-039 showing beneficial trends in mitigating irradiation induced injury.
Deutschmann, Janina [Verfasser], Thomas [Akademischer Betreuer] Gramberg, and Robert [Gutachter] Slany. "Regulatory Mechanism of the Innate Restriction Factor SAMHD1 in Herpesviral Infections / Janina Deutschmann ; Gutachter: Robert Slany ; Betreuer: Thomas Gramberg." Erlangen : Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), 2020. http://d-nb.info/1221370456/34.
Full textAbe, Junya. "A nationwide survey of Aicardi-Goutieres syndrome patients identifies a strong association between dominant TREX1 mutations and chilblain lesions: Japanese cohort study." Kyoto University, 2014. http://hdl.handle.net/2433/188647.
Full textHerrmann, Alexandra [Verfasser], Thomas [Akademischer Betreuer] Gramberg, and Lars [Gutachter] Nitschke. "The role of SAMHD1 in restriction and immune sensing of retroviruses and retroelements / Alexandra Herrmann ; Gutachter: Lars Nitschke ; Betreuer: Thomas Gramberg." Erlangen : Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), 2018. http://d-nb.info/1164768514/34.
Full textMartinat, Charlotte. "Rôle de la sumoylation dans les activités de SAMHD1, un facteur de restriction du VIH-1 dans les cellules non cyclantes." Thesis, Sorbonne Paris Cité, 2018. http://www.theses.fr/2018USPCC246.
Full textSince its discovery seven years ago, SAMHD1 has emerged as an important cellular factor that limits the replication of the Human immunodeficiency virus type 1 (HIV-1) at the reverse transcription step in non-cycling immune cells. HIV-2 and some SIV overcome this restriction by encoding the Vpx protein, which bridges SAMHD1 to the proteasomal degradation pathway. A wealth of experimental evidence indicates that SAMHD1 triphosphohydrolase (dNTPAse) activity, which is responsible for cellular dNTP pools depletion, accounts for the premature termination of viral replication. Notably, SAMHD1 expression is not sufficient to render any tested cell type resistant to HIV-1. Besides, there is no strict link between SAMHD1 capacity to deplete dNTP pools and its neutralizing function. Phosphorylation of residue T592 is proposed to downregulate the antiviral function of SAMHD1 in cycling cells. However, the analysis of phosphomimetic or unphosphorytable mutants of SAMHD1 leads to contradictory results. Altogether, these data suggest that SAMHD1-mediated restriction may neither exclusively rely on its dNTPase activity, nor solely depend on the phosphorylation status of T592.We have demonstrated that SAMHD1 undergoes SUMOylation, i.e. a post-translational modification consisting in the reversible conjugation of SUMO on a target protein; and have identified the major sites of modification. Our results show that mutations preventing SAMHD1 SUMOylation, in particular at residue K595 that lies close to the phosphorytable T592 site, inhibit its antiviral properties without impairing its dNTPase activity. Notably, an analogous phenotype is observed upon deletion of SAMHD1 C-terminus (Δ595-626). Based on these data, we speculate that phosphorytable T592 and SUMOylated K595 residues are part of an interface in SAMHD1 C-terminal tail that is responsible for the recruitment of still unknown cofactor(s) involved in the mechanism of HIV-1 infection restriction. Our work highlights a novel aspect of SAMHD1 regulation and participates to the characterization of molecular basis underlying its antiviral function. The identification of one or several cellular partners will allow a better understanding of retroviral restriction mechanism and could serve as new therapeutic targets to fight HIV-1 infection
Wichit, Sineewanlaya. "Rôle du cholestérol, de la protéine SAMHD1 et de la salive d’Aedes aegypti dans l’infection des cellules cutanées par le virus Chikungunya." Thesis, Montpellier, 2017. http://www.theses.fr/2017MONTT037.
Full textChikungunya virus (CHIKV) is a re-emerging mosquito-borne alphavirus that has been spread worldwide. The dissemination of this virus is a threat to human health since there is no approved vaccine or appropriate antiviral agents to control viral infection. The global expansion of the virus is preceded by biting of infected Aedes mosquitos, which injects saliva containing the virus into the skin of the human host. Searching for effective antiviral compounds and understanding of the molecular mechanisms involved in host-virus or vector-virus-host interactions are crucial for controlling viral spread.Using different molecular and cellular strategies, we demonstrated that the FDA approved drug, imipramine, which has the capability to disturb intracellular cholesterol transport inhibits CHIKV replication in human skin fibroblasts. Imipramine was found to affect both the fusion and replication steps of the viral life cycle. Moreover, it also strongly inhibited the replication of several Flaviviridae family members, including Zika, West Nile and Dengue virus. We have also determined the global proteomic profile of Chikungunya and Zika virus infected human skin fibroblasts, and found that several interferon-stimulated proteins and antiviral response proteins are significantly up-regulated in the infected cells. More importantly, our results also provided for the first time a role of SAMHD1 in arbovirus infection of human skin fibroblasts. Finally, we demonstrated that Aedes aegypti saliva enhances CHIKV replication in human skin fibroblasts. To our knowledge, this is the first report showing the importance of Aedes aegypti saliva on promoting CHIKV infection via down regulation of the genes involving type I IFN secretion in the infected human cutaneous cells
Hlawatsch, Julia [Verfasser], and Thomas [Akademischer Betreuer] Langmann. "Sterile alpha motif containing 7 (Samd7) is a novel Crx-regulated transcriptional repressor in the retina / Julia Hlawatsch. Betreuer: Thomas Langmann." Regensburg : Universitätsbibliothek Regensburg, 2013. http://d-nb.info/1044754176/34.
Full textKutzner, Juliane [Verfasser], and Martin [Akademischer Betreuer] Müller. "Dissecting SAMHD1´s role in the type I Interferon induced early block to HIV-1 infection and its connection to cancer / Juliane Kutzner ; Betreuer: Martin Müller." Heidelberg : Universitätsbibliothek Heidelberg, 2019. http://d-nb.info/1197904344/34.
Full textVijayaraghavan, Balaje. "Identification and characterization of protein-protein interactions in the nuclear envelope." Doctoral thesis, Stockholms universitet, Institutionen för neurokemi, 2017. http://urn.kb.se/resolve?urn=urn:nbn:se:su:diva-148432.
Full textAt the time of the doctoral defense, the following papers were unpublished and had a status as follows: Paper 3: Manuscript. Paper 4: Manuscript.
Nishimura, Yasumitsu. "Insufficient IL-2 production from splenic CD4[+] T cells causes impaired cell proliferation and early apoptosis in SAMP1, a strain of senescence-accelerated mouse." Kyoto University, 2002. http://hdl.handle.net/2433/149355.
Full textAl-shehabi, Hussein [Verfasser]. "The role of human SAMHD1 in restricting porcine endogenous retroviruses (PERVs) and the innate immune response to PERV infection in human primary immune cells / Hussein Ali Nasser Al-shehabi." Berlin : Freie Universität Berlin, 2020. http://d-nb.info/1215099088/34.
Full textAl-shehabi, Hussein Ali Nasser [Verfasser]. "The role of human SAMHD1 in restricting porcine endogenous retroviruses (PERVs) and the innate immune response to PERV infection in human primary immune cells / Hussein Ali Nasser Al-shehabi." Berlin : Freie Universität Berlin, 2020. http://d-nb.info/1215099088/34.
Full textDel, Valle i. Macià Jaume. "Estudi de la relació existent entre les alteracions de la barrera hematoencefàlica i la beta-amiloïdosi en el model murí de senescència accelerada i malaltia d'Alzheimer SAMP8." Doctoral thesis, Universitat de Barcelona, 2010. http://hdl.handle.net/10803/1838.
Full textRadimák, Samuel. "Nástroj pro správu Active Directory." Master's thesis, Vysoké učení technické v Brně. Fakulta informačních technologií, 2016. http://www.nusl.cz/ntk/nusl-255349.
Full textBELNY, MURIEL. "La transformation de suspensions cellulaires de papaver somniferum par agrobacterium tumefaciens avec le gene sam1 d'arabidopsis thaliana codant pour la sam synthetase." Amiens, 1995. http://www.theses.fr/1995AMIEP051.
Full textGeorgeon, Chartier Carole. "Evaluation des effets du vieillissement sur la signalisation calcique des cellules musculaires lisses des artères cérébrales dans les modèles murins C57BL6/J, SAMR1 et SAMP8 dans des conditions normales et sous restriction calorique." Thesis, Bordeaux 1, 2012. http://www.theses.fr/2012BOR14692/document.
Full textDuring aging, cerebral arteries undergo structural and functional changes, particularly in smooth muscle cells (SMC). SMC is responsible for maintaining vascular reactivity via calcium signaling involving different actors and can regulate two phenomena: contraction and relaxation. These actors regroup channels (CCVD, RYR, IP3R) calcium pumps (SERCA, PMCA, NCX, STIM / ORAI) and their regulators (PLB, FKBP12.6, TRPP2, SARAF, TRIC). Caloric restriction (CR) appears as a factor in delaying aging and its pathologies. Our work is strongly involved in the study of calcium signaling in SMC, focusing on genomic and functional alterations during aging of cerebral arteries in mice C57BL6/J. We were able to demonstrate an altered calcium signaling, which is partly through modulation of gene and protein expression levels of calcium channels and pumps involved in this phenomenon, and a functional change in terms of calcium signals and contraction. After 5 months under RC, it was highlighted a slow calcium signaling alterations associated with aging and a decrease of SMC oxidation by SAMP8
Salim, Sa'ad Yislam. "Mucosal dendritic cells in inflammatory bowel disease." Doctoral thesis, Linköpings universitet, Kirurgi, 2009. http://urn.kb.se/resolve?urn=urn:nbn:se:liu:diva-52234.
Full textElias, Pedro Nuno Abrantes Oliveira. "SAMDI : Sistema de Alerta e Monitorização de Dosimetria Individual." Master's thesis, 2014. http://hdl.handle.net/10400.26/12947.
Full textOlson, Timothy Steven. "Lymphocyte and epithelium contributions to Crohn's Disease studied in the SAMP1/YitFc murine ileitis model." 2005. http://gateway.proquest.com/openurl?url_ver=Z39.88-2004&res_dat=xri:pqdiss&rft_val_fmt=info:ofi/fmt:kev:mtx:dissertation&rft_dat=xri:pqdiss:3168468.
Full textCheng, Ming-Yuan, and 鄭名淵. "Effect of S-adenosylmethionine decarboxylase (SAMDC) and Wun1 genes on stamen development and pollen germination in tomato." Thesis, 2009. http://ndltd.ncl.edu.tw/handle/86034563001641548349.
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