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Degenerative Diseases of the Nervous System
Published in Philip B. Gorelick, Fernando D. Testai, Graeme J. Hankey, Joanna M. Wardlaw, Hankey's Clinical Neurology, 2020
James A. Mastrianni, Elizabeth A. Harris
MUR-11 deficiency and Nijmegen breakage syndrome: Present with later onset and slower progression. No telangiectasias.Result from deficiencies of other proteins (MUR11 and NBS1, respectively) that are involved in the same DNA repair pathway as ATM.Alpha fetoprotein (AFP) levels may be normal or slightly elevated.
Cutaneous Malignant Melanoma
Published in Dongyou Liu, Handbook of Tumor Syndromes, 2020
The NBS1 (Nijmegen breakage syndrome 1) gene on chromosome 8q21.3 measures 69.8 kb in length and encodes a 754 aa, 84.9 kDa protein (NBN or nibrin, also referred to as p95). Nibrin interacts with MRE11 and RAD50 to form the MRN complex, which possesses single-strand endonuclease activity and double-strand-specific 3'-5' exonuclease activity and participates in double-strand break (DSB) repair. In addition, nibrin plays a role in the maintenance of telomere length and thus chromosome integrity, and also in the control of intra-S-phase checkpoint. Besides its implication in Nijmegen breakage syndrome, an autosomal recessive disorder characterized by spontaneous chromosomal instability, immunodeficiency, and predisposition to cancer, the NBS1 gene may be also involved in malignant melanoma.
Irradiation-induced damage and the DNA damage response
Published in Michael C. Joiner, Albert J. van der Kogel, Basic Clinical Radiobiology, 2018
Conchita Vens, Marianne Koritzinsky, Bradly G. Wouters
The nature of the lesion dictates the presence of the initial damage-sensing protein. For example, base lesions are recognized by specific glycosylases that are designed to identify and remove the damaged base, while the loss of bases or phosphodiester bonds within DNA quickly activates poly (ADP-ribosylation)-polymerases (PARPs). DSBs are recognized by the MRN complex, consisting of three proteins: MRE11, RAD50 and NBS1. Notably, the NBS1 protein is the product of the gene that is mutated in Nijmegen breakage syndrome (NBS). As its central function in DSB recognition and repair suggests, patients with this syndrome are radiosensitive. The Ku proteins (Ku70 and 80) can also recognize and efficiently bind the ends of DSBs. Single-stranded DNA regions generated during replication or during DSBR are coated by the RPA complex. These initial DNA damage sensing events influence repair pathway choice and dictate DDR signalling through engaging different signal transduction proteins and mechanisms.
The crosstalk between DNA damage response components and DNA-sensing innate immune signaling pathways
Published in International Reviews of Immunology, 2022
Feng Lin, Yan-Dong Tang, Chunfu Zheng
In herpes simplex virus type I (HSV-1) infected cells, cGAS interacts with IFI16 in the nucleus and promotes its stability to potentiate the DNA sensing innate immunity. While in plasmid DNA transfected cells, cGAS initiates the initial response to produce cGAMP, which activates the STING-mediated innate immune signaling pathway [25]. These results argue that cGAS activation may depend on the physicochemical structure of binding DNA or coordinate with IFI16 or other DDR components. NBS1 is a component of the MRE11 complex involving DDR and genome stability maintenance. NBS1 does not have any known enzymatic activities, but its physical residence on the cytosolic chromatin segments might interact with cGAS and counteract cGAS binding to cytosolic chromatin fragments to initiate the cGAS-mediated cytosolic DNA sensing signal pathway, which is under investigation in our lab. Hence, additional evidence is required to precisely identify the roles of NBS1 in the regulation of the cGAS-mediated cytosolic DNA sensing pathway. Inhibitor of bromodomain protein 4 (BRD4), which is mainly responsible for chromatin remodeling, has recently been reported to participate in innate immune responses. BRD4 inhibition leads to the dsDNA releasing from the mitochondria or the nucleus into the cytoplasm, which is recognized by DNA sensor cGAS and activates the antiviral innate immunity [30]. Thereby, it is tempting to speculate that BRD4 could act as a negative regulator of the cGAS-STING signaling pathway to prevent over-reactive innate immune signaling.
Ataxia-telangiectasia: epidemiology, pathogenesis, clinical phenotype, diagnosis, prognosis and management
Published in Expert Review of Clinical Immunology, 2020
Parisa Amirifar, Mohammad Reza Ranjouri, Martin Lavin, Hassan Abolhassani, Reza Yazdani, Asghar Aghamohammadi
ATM is the most frequently reported gene related to A-T clinical manifestations. However, a few cases have been attributed to MRE11 deficiency in early reports, and a minority of patients do not yet have a monogenic cause. Mutations in MRE11 were subsequently shown to be associated with a related but distinct disorder [23]. The ATM gene contains 66 exons (spanning 150 kb of genomic DNA) with 12 protein-encoding transcripts making a range of products from 93 to 3056 amino acids. The full-length ATM protein plays a major role in the molecular response to DNA-DSBs. ATM is rapidly activated by DNA damage and recruited to sites of damage by the MRN complex (MRE11-RAD50-NBS1) via its interaction with the C-terminal domain of NBS1. ATM activation is linked with different posttranslational modifications of the protein, including autophosphorylation at several different sites (Figure 1) [24,25].
A case of premature ovarian insufficiency in Nijmegen breakage syndrome patient and review of literature. From gene mutation to clinical management
Published in Gynecological Endocrinology, 2019
Anna Szeliga, Aleksandra Zysnarska, Zuzanna Szklarska, Ewelina Truszkowska, Agnieszka Podfigurna, Adam Czyzyk, Andrea R. Genazzani, Krystyna Chrzanowska, Blazej Meczekalski
Following the treatment, we observed a decreasing serum concentration of FSH and an increasing level of E2. Other assessed hormones (TSH, fT4, DHEA-S, insulin, and testosterone) remained within reference values. Unfortunately, there are no examples or evaluations of hormone replacement therapy treatment in NBS patients, so there was no possibility for us to compare our results with other analyses. Nevertheless, HRT is advised by other researchers in order to prevent negative effects of estrogen deficiency on cardiovascular system [1]. Other long-term consequence of POI in NBS patients is infertility, in long-term observational studies there was no case of pregnancy in this group of patients [5]. Chrzanowska et al. have confirmed for the first time that POI in the form of hypergonadotropic hypogonadism, besides microcephaly, is the hallmark manifestation found in all girls and young women with NBS [5]. Animal studies provide also results which helps to understand mechanism of ovarian dysfunction in NBS. Difilipantonio et al. showed that Nbs1 protein is necessary for the normal meiotic division [11].