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RNA Biology Sep 2017Adenosine deaminases acting on RNA (ADARs) are zinc-containing enzymes that deaminate adenosine bases to inosines within dsRNA regions in transcripts. In short,... (Review)
Review
Adenosine deaminases acting on RNA (ADARs) are zinc-containing enzymes that deaminate adenosine bases to inosines within dsRNA regions in transcripts. In short, structured dsRNA hairpins individual adenosine bases may be targeted specifically and edited with up to one hundred percent efficiency, leading to the production of alternative protein variants. However, the majority of editing events occur within longer stretches of dsRNA formed by pairing of repetitive sequences. Here, many different adenosine bases are potential targets but editing efficiency is usually much lower. Recent work shows that ADAR-mediated RNA editing is also required to prevent aberrant activation of antiviral innate immune sensors that detect viral dsRNA in the cytoplasm. Missense mutations in the ADAR1 RNA editing enzyme cause a fatal auto-inflammatory disease, Aicardi-Goutières syndrome (AGS) in affected children. In addition RNA editing by ADARs has been observed to increase in many cancers and also can contribute to vascular disease. Thus the role of RNA editing in the progression of various diseases can no longer be ignored. The ability of ADARs to alter the sequence of RNAs has also been used to artificially target model RNAs in vitro and in cells for RNA editing. Potentially this approach may be used to repair genetic defects and to alter genetic information at the RNA level. In this review we focus on the role of ADARs in disease development and progression and on their potential use to artificially modify RNAs in a targeted manner.
Topics: Adenosine Deaminase; Animals; Disease Susceptibility; Humans; Immunity; Mammals; RNA Editing; RNA Stability
PubMed: 28346055
DOI: 10.1080/15476286.2017.1306173 -
Trends in Biochemical Sciences Sep 2021Modified bases act as marks on cellular RNAs so that they can be distinguished from foreign RNAs, reducing innate immune responses to endogenous RNA. In humans,... (Review)
Review
Modified bases act as marks on cellular RNAs so that they can be distinguished from foreign RNAs, reducing innate immune responses to endogenous RNA. In humans, mutations giving reduced levels of one base modification, adenosine-to-inosine deamination, cause a viral infection mimic syndrome, a congenital encephalitis with aberrant interferon induction. These Aicardi-Goutières syndrome 6 mutations affect adenosine deaminase acting on RNA 1 (ADAR1), which generates inosines in endogenous double-stranded (ds)RNA. The inosine base alters dsRNA structure to prevent aberrant activation of antiviral cytosolic helicase RIG-I-like receptors. We review how effects of inosines, ADARs, and other modified bases have been shown to be important in innate immunity and cancer.
Topics: Adenosine Deaminase; Humans; Immunity, Innate; RNA Editing; RNA, Double-Stranded; RNA-Binding Proteins; Transcriptome
PubMed: 33736931
DOI: 10.1016/j.tibs.2021.02.002 -
Cell Reports Nov 2023Cancer evades host immune surveillance by virtue of poor immunogenicity. Here, we report an immune suppressor, designated as PTIR1, that acts as a promotor of tumor...
Cancer evades host immune surveillance by virtue of poor immunogenicity. Here, we report an immune suppressor, designated as PTIR1, that acts as a promotor of tumor immune resistance. PTIR1 is selectively induced in human cancers via alternative splicing of DDX58 (RIG-I), and its induction is closely related to poor outcome in patients with cancer. Through blocking the recruitment of leukocytes, PTIR1 facilitates cancer immune escape and tumor-intrinsic resistance to immunotherapeutic treatments. Unlike RIG-I, PTIR1 is capable of binding to the C terminus of UCHL5 and activates its ubiquitinating function, which in turn inhibits immunoproteasome activity and limits neoantigen processing and presentation, consequently blocking T cell recognition and attack against cancer. Moreover, we find that the adenosine deaminase ADAR1 induces A-to-I RNA editing on DDX58 transcript, thus triggering PTIR1 production. Collectively, our data uncover the immunosuppressive role of PTIR1 in tumorigenesis and propose that ADAR1-PTIR1-UCHL5 signaling is a potential cancer immunotherapeutic target.
Topics: Humans; Signal Transduction; Cell Communication; Carcinogenesis; Protein Isoforms; Adenosine Deaminase; DEAD Box Protein 58; Receptors, Immunologic; Ubiquitin Thiolesterase
PubMed: 37934668
DOI: 10.1016/j.celrep.2023.113388 -
Molecular Therapy : the Journal of the... Mar 2018Loss of adenosine deaminase activity leads to severe combined immunodeficiency (ADA-SCID); production and function of T, B, and natural killer (NK) cells are impaired....
Loss of adenosine deaminase activity leads to severe combined immunodeficiency (ADA-SCID); production and function of T, B, and natural killer (NK) cells are impaired. Gene therapy (GT) with an autologous CD34-enriched cell fraction that contains CD34 cells transduced with a retroviral vector encoding the human ADA cDNA sequence leads to immune reconstitution in most patients. Here, we report short- and medium-term safety analyses from 18 patients enrolled as part of single-arm, open-label studies or compassionate use programs. Survival was 100% with a median of 6.9 years follow-up (range, 2.3 to 13.4 years). Adverse events were mostly grade 1 or grade 2 and were reported by all 18 patients following GT. Thirty-nine serious adverse events (SAEs) were reported by 15 of 18 patients; no SAEs were considered related to GT. The most common adverse events reported post-GT include upper respiratory tract infection, gastroenteritis, rhinitis, bronchitis, oral candidiasis, cough, neutropenia, diarrhea, and pyrexia. Incidence rates for all of these events were highest during pre-treatment, treatment, and/or 3-month follow-up and then declined over medium-term follow-up. GT did not impact the incidence of neurologic/hearing impairments. No event indicative of leukemic transformation was reported.
Topics: Adenosine Deaminase; Agammaglobulinemia; Autoimmunity; Child; Child, Preschool; Combined Modality Therapy; Enzyme Replacement Therapy; Follow-Up Studies; Gene Expression; Genetic Therapy; Genetic Vectors; Hematopoietic Stem Cell Transplantation; Humans; Infant; Male; Phenotype; Severe Combined Immunodeficiency; Transgenes; Treatment Outcome
PubMed: 29433935
DOI: 10.1016/j.ymthe.2017.12.022 -
Veterinary Research Communications Sep 2023Enzyme adenosine deaminase (ADA) is a marker of inflammation in domestic animals, but it is unclear whether it is a reliable marker of oxidative stress, especially in...
Enzyme adenosine deaminase (ADA) is a marker of inflammation in domestic animals, but it is unclear whether it is a reliable marker of oxidative stress, especially in the transition period in dairy cows. This study aims to assess if ADA and redox status measurements in saliva provide the same utility to detect disease condition as that obtained from serum. Sixty-eight multiparous Holstein cows, between 2 and 3 weeks postpartum were selected. Five study groups were established: control (healthy), and cows with ketosis, mastitis, laminitis, and metritis. The parameters measured were ADA activity, total oxidants (TOS), antioxidants (TAC), and OSi ratio.Regarding redox status, no significant differences arise in both saliva and serum being the correlations negative and not significant. In saliva, ADA activity in healthy cows differs from those with pathological processes, having the lowest activities. In serum, ADA activity is similar in the healthy and ketosis cows, showing the lowest activities meanwhile animals with mastitis, laminitis, or metritis have significantly higher activities. In conclusion, the measurement of ADA activities and redox status in saliva does not give consistent results, being preferable to measure them in serum during the transition period.
Topics: Animals; Cattle; Female; Adenosine Deaminase; Cattle Diseases; Ketosis; Lactation; Mastitis; Milk; Oxidation-Reduction; Postpartum Period; Saliva
PubMed: 36607499
DOI: 10.1007/s11259-023-10069-2 -
International Journal of... 2011It is estimated that approximately 1 percent of babies born per year result from in vitro fertilization and embryo transfer, and other assisted reproductive...
It is estimated that approximately 1 percent of babies born per year result from in vitro fertilization and embryo transfer, and other assisted reproductive technologies. In humans, the exact mechanisms that lead to embryonic attachment to the endometrial epithelium and invasion into the endometrial stroma have not been fully characterized. The aim of the study is to estimate serum total adenosine deaminase and isoenzymes ADA1, ADA2, as well as MMP-2, MMP-3, MMP-13 and MIP-1a as parameters for pregnancy following IVF-ET. The study group comprised seventeen women who conceived (Group A) and nineteen women aged 21-42 years who did not conceive (Group B) after IVF-ET. Blood samples were collected between 09.00 and 10.00 a.m. during IVF-ET treatment at two different periods. The first blood sample was collected before ET and the second sample 14 days after ET. All serum samples were assayed for the MMP-2, MMP-3 MMP-13 and MIP-1a concentrations with ELISA assay. Serum tADA activity was measured by a spectrophotometer using adenosine as the substrate (Method by Giusti). According to our results it was demonstrated that women who successfully conceived after IVF-ET showed significantly lower serum concentrations of ADA1, MMP-2, MMP-3 and higher serum concentration of MMP-13 at 14 days following ET. In conclusion, ADA1 may play a protective role at the hemochorial interface. Thus, our results suggest that ADA1 may have a modulatory role in the implantation and duration of the pregnancy. In women with successful or unsuccessful pregnancy compared with normal women the levels of ADA and MMPs may be affected by the exogenous hormone therapy according to the protocol of ovarian stimulation during IVF-ET.
Topics: Adenosine Deaminase; Adult; Biomarkers; Embryo Transfer; Female; Fertilization in Vitro; Humans; Isoenzymes; Metalloproteases; Pregnancy
PubMed: 21496384
DOI: 10.1177/039463201102400104 -
Sensors (Basel, Switzerland) Jul 2018Adenosine deaminase (ADA), able to catalyze the irreversible deamination of adenosine into inosine, can be found in almost all tissues and plays an important role in...
Adenosine deaminase (ADA), able to catalyze the irreversible deamination of adenosine into inosine, can be found in almost all tissues and plays an important role in several diseases. In this work, we developed a label-free fluorescence method for the detection of adenosine deaminase activity and inhibition. In the presence of ADA, ATP has been shown to be hydrolyzed. The ATP aptamer was shown to form a G-quadruplex/thioflavin T (ThT) complex with ThT and exhibited an obvious fluorescence signal. However, the ATP aptamer could bind with ATP and exhibited a low fluorescence signal because of the absence of ADA. This assay showed high sensitivity to ADA with a detection limit of 1 U/L based on an SNR of 3 and got a good linear relationship within the range of 1⁻100 U/L with R² = 0.9909. The LOD is lower than ADA cutoff value (4 U/L) in the clinical requirement and more sensitive than most of the reported methods. This technique exhibited high selectivity for ADA against hoGG I, UDG, RNase H and λexo. Moreover, this strategy was successfully applied for assaying the inhibition of ADA using erythro-9-(2-hydroxy-3-nonyl) adenine (EHNA) and, as such, demonstrated great potential for the future use in the diagnosis of ADA-relevant diseases, particularly in advanced drug development.
Topics: Adenosine Deaminase; Adenosine Deaminase Inhibitors; Biosensing Techniques; Enzyme Assays; Fluorescence; Humans; Limit of Detection; Time Factors
PubMed: 30060448
DOI: 10.3390/s18082441 -
Annual Review of Virology Sep 2021C6 deamination of adenosine (A) to inosine (I) in double-stranded RNA (dsRNA) is catalyzed by a family of enzymes known as ADARs (adenosine deaminases acting on RNA)...
C6 deamination of adenosine (A) to inosine (I) in double-stranded RNA (dsRNA) is catalyzed by a family of enzymes known as ADARs (adenosine deaminases acting on RNA) encoded by three genes in mammals. Alternative promoters and splicing produce two ADAR1 proteins, an interferon-inducible cytoplasmic p150 and a constitutively expressed p110 that like ADAR2 is a nuclear enzyme. ADAR3 lacks deaminase activity. A-to-I editing occurs with both viral and cellular RNAs. Deamination activity is dependent on dsRNA substrate structure and regulatory RNA-binding proteins and ranges from highly site selective with hepatitis D RNA and glutamate receptor precursor messenger RNA (pre-mRNA) to hyperediting of measles virus and polyomavirus transcripts and cellular inverted elements. Because I base-pairs as guanosine instead of A, editing can alter mRNA decoding, pre-mRNA splicing, and microRNA silencing. Editing also alters dsRNA structure, thereby suppressing innate immune responses including interferon production and action.
Topics: Adenosine Deaminase; Animals; RNA Editing; RNA, Double-Stranded; RNA-Binding Proteins; Virus Diseases
PubMed: 33882257
DOI: 10.1146/annurev-virology-091919-065320 -
Frontiers in Immunology 2019Inherited defects in adenosine deaminase (ADA) cause severe immune deficiency, which can be corrected by ADA enzyme replacement therapy (ERT). Additionally,...
Inherited defects in adenosine deaminase (ADA) cause severe immune deficiency, which can be corrected by ADA enzyme replacement therapy (ERT). Additionally, ADA-deficient patients suffer from hearing impairment. We hypothesized that ADA-deficient (-/-) mice also exhibit hearing abnormalities and that ERT from an early age will improve the hearing and immune defects in these mice. Auditory brainstem evoked responses, organ weights, thymocytes numbers, and subpopulations, lymphocytes in peripheral blood as well as T lymphocytes in spleen were analyzed in ADA-/- and ADA-proficient littermate post-partum (pp). The cochlea was visualized by scanning electron microscopy (SEM). The effects of polyethylene glycol conjugated ADA (PEG-ADA) ERT or 40% oxygen initiated at 7 days pp on the hearing and immune abnormalities were assessed. Markedly abnormal hearing thresholds responses were found in ADA-/- mice at low and medium tone frequencies. SEM demonstrated extensive damage to the cochlear hair cells of ADA-/- mice, which were splayed, short or missing, correlating with the hearing deficits. The hearing defects were not reversed when hypoxia in ADA-/- mice was corrected. Progressive immune abnormalities were detected in ADA-/- mice from 4 days pp, initially affecting the thymus followed by peripheral lymphocytes and T cells in the spleen. ERT initiated at 7 days pp significantly improved the hearing of ADA-/- mice as well as the number of thymocytes and T lymphocytes, although not all normalized. ADA deficiency is associated with hearing deficits and damage to cochlear hair cells. Early initiation of ERT improves the hearing and immune abnormalities.
Topics: Adenosine Deaminase; Agammaglobulinemia; Animals; Enzyme Replacement Therapy; Hair Cells, Auditory; Hearing Loss; Mice; Mice, Knockout; Severe Combined Immunodeficiency
PubMed: 30918508
DOI: 10.3389/fimmu.2019.00416 -
Orphanet Journal of Rare Diseases May 2023Deficiency of adenosine deaminase 2 (DADA2) is a rare monogenic autoinflammatory disease, whose clinical phenotype was expanded since the first cases, originally... (Review)
Review
INTRODUCTION
Deficiency of adenosine deaminase 2 (DADA2) is a rare monogenic autoinflammatory disease, whose clinical phenotype was expanded since the first cases, originally described as mimicker of polyarteritis nodosa, with immunodeficiency and early-onset stroke.
METHODS
A systematic review according to PRISMA approach, including all articles published before the 31st of August 2021 in Pubmed and EMBASE database was performed.
RESULTS
The search identified 90 publications describing 378 unique patients (55.8% male). To date 95unique mutations have been reported. The mean age at disease onset was 92.15 months (range 0-720 months), 32 (8.5%) showed an onset of the first signs/symptoms after 18 years old and 96 (25.4%) after 10 years old. The most frequent clinical characteristics described were cutaneous (67.9%), haematological manifestations (56.3%), recurrent fever (51.3%), neurological as stroke and polyneuropathy (51%), immunological abnormalities (42.3%), arthralgia/arthritis (35.4%), splenomegaly (30.6%), abdominal involvement (29.8%), hepatomegaly (23.5%), recurrent infections (18.5%), myalgia (17.9%), kidney involvement (17.7%) etc. Patients with skin manifestations were older than the others (101.1 months SD ± 116.5, vs. 75.3 SD ± 88.2, p 0.041), while those with a haematological involvement (64.1 months SD ± 75.6 vs. 133.1 SD ± 133.1, p < 0.001) and immunological involvement (73.03 months SD ± 96.9 vs. 103.2 SD ± 112.9, p 0.05) are younger than the others. We observed different correlations among the different clinical manifestations. The use of anti-TNFα and hematopoietic cell stems transplantation (HCST) has improved the current history of the disease.
CONCLUSION
Due to this highly variable phenotype and age of presentation, patients with DADA2 may present to several type of specialists. Given the important morbidity and mortality, early diagnosis and treatment are mandatory.
Topics: Male; Female; Humans; Adenosine Deaminase; Intercellular Signaling Peptides and Proteins; Phenotype; Stroke; Mutation
PubMed: 37179309
DOI: 10.1186/s13023-023-02721-6