Role of DDX1 in the oxidative response of ataxia telangiectasia patient-derived fibroblasts
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...
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| Format: | Article |
| Language: | English |
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Elsevier
2024-02-01
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| Series: | Redox Biology |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2213231723003890 |
| _version_ | 1827583807645024256 |
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| author | Mansi Garg Lei Li Roseline Godbout |
| author_facet | Mansi Garg Lei Li Roseline Godbout |
| author_sort | Mansi Garg |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-08T23:12:07Z |
| format | Article |
| id | doaj.art-0bd6d56566c247568d87b4927a5ec241 |
| institution | Directory Open Access Journal |
| issn | 2213-2317 |
| language | English |
| last_indexed | 2024-03-08T23:12:07Z |
| publishDate | 2024-02-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Redox Biology |
| spelling | doaj.art-0bd6d56566c247568d87b4927a5ec2412023-12-15T07:24:00ZengElsevierRedox Biology2213-23172024-02-0169102988Role of DDX1 in the oxidative response of ataxia telangiectasia patient-derived fibroblastsMansi Garg0Lei Li1Roseline Godbout2Department of Oncology, Cross Cancer Institute, University of Alberta, 11560 University Avenue, Edmonton, Alberta, T6G 1Z2, CanadaDepartment of Oncology, Cross Cancer Institute, University of Alberta, 11560 University Avenue, Edmonton, Alberta, T6G 1Z2, CanadaCorresponding author.; Department of Oncology, Cross Cancer Institute, University of Alberta, 11560 University Avenue, Edmonton, Alberta, T6G 1Z2, CanadaAtaxia 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.http://www.sciencedirect.com/science/article/pii/S2213231723003890Ataxia TelangiectasiaOxidative stressNeurodegenerationDEAD box protein 1ATMRNA protection |
| spellingShingle | Mansi Garg Lei Li Roseline Godbout Role of DDX1 in the oxidative response of ataxia telangiectasia patient-derived fibroblasts Redox Biology Ataxia Telangiectasia Oxidative stress Neurodegeneration DEAD box protein 1 ATM RNA protection |
| title | Role of DDX1 in the oxidative response of ataxia telangiectasia patient-derived fibroblasts |
| title_full | Role of DDX1 in the oxidative response of ataxia telangiectasia patient-derived fibroblasts |
| title_fullStr | Role of DDX1 in the oxidative response of ataxia telangiectasia patient-derived fibroblasts |
| title_full_unstemmed | Role of DDX1 in the oxidative response of ataxia telangiectasia patient-derived fibroblasts |
| title_short | Role of DDX1 in the oxidative response of ataxia telangiectasia patient-derived fibroblasts |
| title_sort | role of ddx1 in the oxidative response of ataxia telangiectasia patient derived fibroblasts |
| topic | Ataxia Telangiectasia Oxidative stress Neurodegeneration DEAD box protein 1 ATM RNA protection |
| url | http://www.sciencedirect.com/science/article/pii/S2213231723003890 |
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