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Role of DDX1 in the oxidative response of ataxia telangiectasia patient-derived fibroblasts.
- Source :
-
Redox biology [Redox Biol] 2024 Feb; Vol. 69, pp. 102988. Date of Electronic Publication: 2023 Dec 09. - Publication Year :
- 2024
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Abstract
- Ataxia Telangiectasia (A-T) is an inherited autosomal recessive disorder characterized by cerebellar neurodegeneration, radiosensitivity, immunodeficiency and a high incidence of lymphomas. A-T is caused by mutations in the ATM gene. While loss of ATM function in DNA repair explains some aspects of A-T pathophysiology such as radiosensitivity and cancer predisposition, other A-T features such as neurodegeneration imply additional roles for ATM outside the nucleus. Emerging evidence suggests that ATM participates in cellular response to oxidative stress, failure of which contributes to the neurodegeneration associated with A-T. Here, we use fibroblasts derived from A-T patients to investigate whether DEAD Box 1 (DDX1), an RNA binding/unwinding protein that functions downstream of ATM in DNA double strand break repair, also plays a role in ATM-dependent cellular response to oxidative stress. Focusing on DDX1 target RNAs that are associated with neurological disorders and oxidative stress response, we show that ATM is required for increased binding of DDX1 to its target RNAs in the presence of arsenite-induced oxidative stress. Our results indicate that DDX1 functions downstream of ATM by protecting specific mRNAs in the cytoplasm of arsenite-treated cells. In keeping with a role for ATM and DDX1 in oxidative stress, levels of reactive oxygen species (ROS) are increased in ATM-deficient as well as DDX1-depleted cells. We propose that reduced levels of cytoplasmic DDX1 RNA targets sensitizes ATM-deficient cells to oxidative stress resulting in increased cell death. This sensitization would be especially detrimental to long-lived highly metabolically active cells such as neurons providing a possible explanation for the neurodegenerative defects associated with A-T.<br />Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.<br /> (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)
- Subjects :
- Humans
Ataxia Telangiectasia Mutated Proteins genetics
Ataxia Telangiectasia Mutated Proteins metabolism
Oxidative Stress physiology
Fibroblasts metabolism
RNA
Cell Cycle Proteins metabolism
DEAD-box RNA Helicases genetics
DEAD-box RNA Helicases metabolism
Ataxia Telangiectasia genetics
Ataxia Telangiectasia metabolism
Arsenites
Subjects
Details
- Language :
- English
- ISSN :
- 2213-2317
- Volume :
- 69
- Database :
- MEDLINE
- Journal :
- Redox biology
- Publication Type :
- Academic Journal
- Accession number :
- 38096740
- Full Text :
- https://doi.org/10.1016/j.redox.2023.102988