scholarly journals Genetic Risk Variants for Class Switching Recombination Defects in Ataxia-Telangiectasia Patients

2021 ◽  
Author(s):  
Parisa Amirifar ◽  
Mahya Mehrmohamadi ◽  
Mohammad Reza Ranjouri ◽  
Seyed Mohammad Akrami ◽  
Nima Rezaei ◽  
...  
Keyword(s):  
Ataxia Telangiectasia ◽  
Antigen Processing ◽  
Autosomal Recessive Disorder ◽  
Clinical Severity ◽  
Dna Double Strand Breaks ◽  
Class Switching ◽  
Modifying Factors ◽  
Risk Variants ◽  
Presentation Pathway ◽  
Class Switching Recombination

Abstract Background Ataxia-telangiectasia (A-T) is a rare autosomal recessive disorder caused by mutations in the ataxia telangiectasia mutated (ATM) gene. A-T patients manifest considerable variability in clinical and immunological features, suggesting the presence of genetic modifying factors. A striking heterogeneity has been observed in class switching recombination (CSR) in A-T patients which cannot be explained by the severity of ATM mutations. Methods To investigate the cause of variable CSR in A-T patients, we applied whole-exome sequencing (WES) in 20 A-T patients consisting of 10 cases with CSR defect (CSR-D) and 10 controls with normal CSR (CSR-N). Comparative analyses on modifier variants found in the exomes of these two groups of patients were performed. Results For the first time, we identified some variants in the exomes of the CSR-D group that were significantly associated with antigen processing and presentation pathway. Moreover, in this group of patients, the variants in four genes involved in DNA double-strand breaks (DSB) repair signaling, in particular, XRCC3 were observed, suggesting an association with CSR defect. Conclusion Additional impact of certain variants, along with ATM mutations, may explain the heterogeneity in CSR defect phenotype among A-T patients. It can be concluded that genetic modulators play an important role in the course of A-T disease and its clinical severity.

scholarly journals NADPH oxidase 4 is a critical mediator in Ataxia telangiectasia disease

2015 ◽  
Vol 112 (7) ◽  
pp. 2121-2126 ◽  
Author(s):  
Urbain Weyemi ◽  
Christophe E. Redon ◽  
Towqir Aziz ◽  
Rohini Choudhuri ◽  
Daisuke Maeda ◽  
...  
Keyword(s):  
T Cells ◽  
Nadph Oxidase ◽  
Ataxia Telangiectasia ◽  
Oxidative Dna Damage ◽  
Replicative Senescence ◽  
Specific Inhibitor ◽  
Autosomal Recessive Disorder ◽  
Dna Double Strand Breaks ◽  
Nadph Oxidase 4 ◽  
Atm Protein

Ataxia telangiectasia (A-T), a rare autosomal recessive disorder characterized by progressive cerebellar degeneration and a greatly increased incidence of cancer among other symptoms, is caused by a defective or missing ataxia telangiectasia mutated (ATM) gene. The ATM protein has roles in DNA repair and in the regulation of reactive oxygen species (ROS). Here, we provide, to our knowledge, the first evidence that NADPH oxidase 4 (NOX4) is involved in manifesting A-T disease. We showed that NOX4 expression levels are higher in A-T cells, and that ATM inhibition leads to increased NOX4 expression in normal cells. A-T cells exhibit elevated levels of oxidative DNA damage, DNA double-strand breaks and replicative senescence, all of which are partially abrogated by down-regulation of NOX4 with siRNA. Sections of degenerating cerebelli from A-T patients revealed elevated NOX4 levels. ATM-null mice exhibit A-T disease but they die from cancer before the neurological symptoms are manifested. Injecting Atm-null mice with fulvene-5, a specific inhibitor of NOX4 and NADPH oxidase 2 (NOX2), decreased their elevated cancer incidence to that of the controls. We conclude that, in A-T disease in humans and mice, NOX4 may be critical mediator and targeting it will open up new avenues for therapeutic intervention in neurodegeneration.

scholarly journals Mechanisms Underlying the Suppression of Chromosome Rearrangements by Ataxia-Telangiectasia Mutated

Genes ◽  
2021 ◽  
Vol 12 (8) ◽  
pp. 1232
Author(s):  
Motohiro Yamauchi
Keyword(s):  
Ataxia Telangiectasia ◽  
Cellular Response ◽  
Chromosome Rearrangement ◽  
Autosomal Recessive Disorder ◽  
Cellular Level ◽  
Chromosome Rearrangements ◽  
Dna Double Strand Breaks ◽  
Ataxia Telangiectasia Mutated ◽  
Structural Variations ◽  
Cellular Phenotypes

Chromosome rearrangements are structural variations in chromosomes, such as inversions and translocations. Chromosome rearrangements have been implicated in a variety of human diseases. Ataxia-telangiectasia (A-T) is an autosomal recessive disorder characterized by a broad range of clinical and cellular phenotypes. At the cellular level, one of the most prominent features of A-T cells is chromosome rearrangement, especially that in T lymphocytes. The gene that is defective in A-T is ataxia-telangiectasia mutated (ATM). The ATM protein is a serine/threonine kinase and plays a central role in the cellular response to DNA damage, particularly DNA double-strand breaks. In this review, the mechanisms by which ATM suppresses chromosome rearrangements are discussed.

scholarly journals Requirement of ATM in Phosphorylation of the Human p53 Protein at Serine 15 following DNA Double-Strand Breaks

1999 ◽  
Vol 19 (4) ◽  
pp. 2828-2834 ◽  
Author(s):  
Kazumi Nakagawa ◽  
Yoichi Taya ◽  
Katsuyuki Tamai ◽  
Masaru Yamaizumi
Keyword(s):  
Heat Shock ◽  
Ataxia Telangiectasia ◽  
Xeroderma Pigmentosum ◽  
P53 Protein ◽  
Double Strand Breaks ◽  
Nuclear Accumulation ◽  
Dna Double Strand Breaks ◽  
Strand Breaks ◽  
Absolute Requirement ◽  
Primary Fibroblasts

ABSTRACT Microinjection of the restriction endonuclease HaeIII, which causes DNA double-strand breaks with blunt ends, induces nuclear accumulation of p53 protein in normal and xeroderma pigmentosum (XP) primary fibroblasts. In contrast, this induction of p53 accumulation is not observed in ataxia telangiectasia (AT) fibroblasts. HaeIII-induced p53 protein in normal fibroblasts is phosphorylated at serine 15, as determined by immunostaining with an antibody specific for phosphorylated serine 15 of p53. This phosphorylation correlates well with p53 accumulation. Treatment with lactacystin (an inhibitor of the proteasome) or heat shock leads to similar levels of p53 accumulation in normal and AT fibroblasts, but the p53 protein lacks a phosphorylated serine 15. Following microinjection of HaeIII into lactacystin-treated normal fibroblasts, lactacystin-induced p53 protein is phosphorylated at serine 15 and stabilized even in the presence of cycloheximide. However, neither stabilization nor phosphorylation at serine 15 is observed in AT fibroblasts under the same conditions. These results indicate the significance of serine 15 phosphorylation for p53 stabilization after DNA double-strand breaks and an absolute requirement for ATM in this phosphorylation process.

scholarly journals DNA structure-specific priming of ATR activation by DNA-PKcs

2013 ◽  
Vol 202 (3) ◽  
pp. 421-429 ◽  
Author(s):  
Sophie Vidal-Eychenié ◽  
Chantal Décaillet ◽  
Jihane Basbous ◽  
Angelos Constantinou
Keyword(s):  
Dna Damage ◽  
Ataxia Telangiectasia ◽  
Protein A ◽  
Dna Structure ◽  
Specific Response ◽  
Dna Double Strand Breaks ◽  
Strand Breaks ◽  
Synergistic Activation ◽  
Dependent Protein ◽  
Specific Priming

Three phosphatidylinositol-3-kinase–related protein kinases implement cellular responses to DNA damage. DNA-dependent protein kinase catalytic subunit (DNA-PKcs) and ataxia-telangiectasia mutated respond primarily to DNA double-strand breaks (DSBs). Ataxia-telangiectasia and RAD3-related (ATR) signals the accumulation of replication protein A (RPA)–covered single-stranded DNA (ssDNA), which is caused by replication obstacles. Stalled replication intermediates can further degenerate and yield replication-associated DSBs. In this paper, we show that the juxtaposition of a double-stranded DNA end and a short ssDNA gap triggered robust activation of endogenous ATR and Chk1 in human cell-free extracts. This DNA damage signal depended on DNA-PKcs and ATR, which congregated onto gapped linear duplex DNA. DNA-PKcs primed ATR/Chk1 activation through DNA structure-specific phosphorylation of RPA32 and TopBP1. The synergistic activation of DNA-PKcs and ATR suggests that the two kinases combine to mount a prompt and specific response to replication-born DSBs.

scholarly journals ATM’s Role in the Repair of DNA Double-Strand Breaks

Genes ◽  
2021 ◽  
Vol 12 (9) ◽  
pp. 1370
Author(s):  
Atsushi Shibata ◽  
Penny A. Jeggo
Keyword(s):  
Stress Responses ◽  
Ataxia Telangiectasia ◽  
Cell Cycle Checkpoint ◽  
Double Strand Breaks ◽  
Multiple Roles ◽  
Dna Double Strand Breaks ◽  
Ataxia Telangiectasia Mutated ◽  
Dsb Repair ◽  
Strand Breaks ◽  
Cycle Checkpoint

Ataxia telangiectasia mutated (ATM) is a central kinase that activates an extensive network of responses to cellular stress via a signaling role. ATM is activated by DNA double strand breaks (DSBs) and by oxidative stress, subsequently phosphorylating a plethora of target proteins. In the last several decades, newly developed molecular biological techniques have uncovered multiple roles of ATM in response to DNA damage—e.g., DSB repair, cell cycle checkpoint arrest, apoptosis, and transcription arrest. Combinational dysfunction of these stress responses impairs the accuracy of repair, consequently leading to dramatic sensitivity to ionizing radiation (IR) in ataxia telangiectasia (A-T) cells. In this review, we summarize the roles of ATM that focus on DSB repair.

scholarly journals Structural basis of homologous recombination

2019 ◽  
Vol 77 (1) ◽  
pp. 3-18 ◽  
Author(s):  
Yueru Sun ◽  
Thomas J. McCorvie ◽  
Luke A. Yates ◽  
Xiaodong Zhang
Keyword(s):  
Breast Cancer ◽  
Electron Microscopy ◽  
Homologous Recombination ◽  
Ataxia Telangiectasia ◽  
Structural Information ◽  
Homology Search ◽  
Structural Basis ◽  
Cancer Type ◽  
Dna Double Strand Breaks ◽  
Breast Cancer Type

AbstractHomologous recombination (HR) is a pathway to faithfully repair DNA double-strand breaks (DSBs). At the core of this pathway is a DNA recombinase, which, as a nucleoprotein filament on ssDNA, pairs with homologous DNA as a template to repair the damaged site. In eukaryotes Rad51 is the recombinase capable of carrying out essential steps including strand invasion, homology search on the sister chromatid and strand exchange. Importantly, a tightly regulated process involving many protein factors has evolved to ensure proper localisation of this DNA repair machinery and its correct timing within the cell cycle. Dysregulation of any of the proteins involved can result in unchecked DNA damage, leading to uncontrolled cell division and cancer. Indeed, many are tumour suppressors and are key targets in the development of new cancer therapies. Over the past 40 years, our structural and mechanistic understanding of homologous recombination has steadily increased with notable recent advancements due to the advances in single particle cryo electron microscopy. These have resulted in higher resolution structural models of the signalling proteins ATM (ataxia telangiectasia mutated), and ATR (ataxia telangiectasia and Rad3-related protein), along with various structures of Rad51. However, structural information of the other major players involved, such as BRCA1 (breast cancer type 1 susceptibility protein) and BRCA2 (breast cancer type 2 susceptibility protein), has been limited to crystal structures of isolated domains and low-resolution electron microscopy reconstructions of the full-length proteins. Here we summarise the current structural understanding of homologous recombination, focusing on key proteins in recruitment and signalling events as well as the mediators for the Rad51 recombinase.

scholarly journals Relevance of viral context and diversity of antigen-processing routes for respiratory syncytial virus cytotoxic T-lymphocyte epitopes

2008 ◽  
Vol 89 (9) ◽  
pp. 2194-2203 ◽  
Author(s):  
Carolina Johnstone ◽  
Sara Guil ◽  
Miguel A. Rico ◽  
Blanca García-Barreno ◽  
Daniel López ◽  
...  
Keyword(s):  
Respiratory Syncytial Virus ◽  
Mhc Class I ◽  
Antigen Processing ◽  
Cytotoxic T Lymphocyte ◽  
Class I ◽  
F Protein ◽  
Mhc Class I Molecule ◽  
Presentation Pathway ◽  
Syncytial Virus ◽  
In Cells

Antigen processing of respiratory syncytial virus (RSV) fusion (F) protein epitopes F85–93 and F249–258 presented to cytotoxic T-lymphocytes (CTLs) by the murine major histocompatibility complex (MHC) class I molecule Kd was studied in different viral contexts. Epitope F85–93 was presented through a classical endogenous pathway dependent on the transporters associated with antigen processing (TAP) when the F protein was expressed from either RSV or recombinant vaccinia virus (rVACV). At least in cells infected with rVACV encoding either natural or cytosolic F protein, the proteasome was required for epitope processing. In cells infected with rVACV encoding the natural F protein, an additional endogenous TAP-independent presentation pathway was found for F85–93. In contrast, epitope F249–258 was presented only through TAP-independent pathways, but presentation was brefeldin A sensitive when the F protein was expressed from RSV, or mostly resistant when expressed from rVACV. Therefore, antigen-processing pathways with different mechanisms and subcellular localizations are accessible to individual epitopes presented by the same MHC class I molecule and processed from the same protein but in different viral contexts. This underscores both the diversity of pathways available and the influence of virus infection on presentation of epitopes to CTLs.

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