The splicing factor DHX38 enables retinal development through safeguarding genome integrity
Summary: DEAH-Box Helicase 38 (DHX38) is a pre-mRNA splicing factor and also a disease-causing gene of autosomal recessive retinitis pigmentosa (arRP). The role of DHX38 in the development and maintenance of the retina remains largely unknown. In this study, by using the dhx38 knockout zebrafish mod...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2023-11-01
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| Series: | iScience |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2589004223021806 |
| _version_ | 1797660101035687936 |
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| author | Kui Sun Yunqiao Han Jingzhen Li Shanshan Yu Yuwen Huang Yangjun Zhang Jamas Reilly Jiayi Tu Pan Gao Danna Jia Xiang Chen Hualei Hu Mengmeng Ren Pei Li Jiong Luo Xiang Ren Xianqin Zhang Xinhua Shu Fei Liu Mugen Liu Zhaohui Tang |
| author_facet | Kui Sun Yunqiao Han Jingzhen Li Shanshan Yu Yuwen Huang Yangjun Zhang Jamas Reilly Jiayi Tu Pan Gao Danna Jia Xiang Chen Hualei Hu Mengmeng Ren Pei Li Jiong Luo Xiang Ren Xianqin Zhang Xinhua Shu Fei Liu Mugen Liu Zhaohui Tang |
| author_sort | Kui Sun |
| collection | DOAJ |
| description | Summary: DEAH-Box Helicase 38 (DHX38) is a pre-mRNA splicing factor and also a disease-causing gene of autosomal recessive retinitis pigmentosa (arRP). The role of DHX38 in the development and maintenance of the retina remains largely unknown. In this study, by using the dhx38 knockout zebrafish model, we demonstrated that Dhx38 deficiency causes severe differentiation defects and apoptosis of retinal progenitor cells (RPCs) through disrupted mitosis and increased DNA damage. Furthermore, we found a significant accumulation of R-loops in the dhx38-deficient RPCs and human cell lines. Finally, we found that DNA replication stress is the prerequisite for R-loop-induced DNA damage in the DHX38 knockdown cells. Taken together, our study demonstrates a necessary role of DHX38 in the development of retina and reveals a DHX38/R-loop/replication stress/DNA damage regulatory axis that is relatively independent of the known functions of DHX38 in mitosis control. |
| first_indexed | 2024-03-11T18:24:53Z |
| format | Article |
| id | doaj.art-40b0dbf83a734a25a3991847a39c4778 |
| institution | Directory Open Access Journal |
| issn | 2589-0042 |
| language | English |
| last_indexed | 2024-03-11T18:24:53Z |
| publishDate | 2023-11-01 |
| publisher | Elsevier |
| record_format | Article |
| series | iScience |
| spelling | doaj.art-40b0dbf83a734a25a3991847a39c47782023-10-14T04:45:10ZengElsevieriScience2589-00422023-11-012611108103The splicing factor DHX38 enables retinal development through safeguarding genome integrityKui Sun0Yunqiao Han1Jingzhen Li2Shanshan Yu3Yuwen Huang4Yangjun Zhang5Jamas Reilly6Jiayi Tu7Pan Gao8Danna Jia9Xiang Chen10Hualei Hu11Mengmeng Ren12Pei Li13Jiong Luo14Xiang Ren15Xianqin Zhang16Xinhua Shu17Fei Liu18Mugen Liu19Zhaohui Tang20Key Laboratory of Molecular Biophysics of the Ministry of Education, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, Hubei 430074, P.R. ChinaKey Laboratory of Molecular Biophysics of the Ministry of Education, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, Hubei 430074, P.R. ChinaResearch Center for Biochemistry and Molecular Biology, Jiangsu Key Laboratory of Brain Disease Bioinformation, Xuzhou Medical University, Xuzhou, Jiangsu 221004, P.R. ChinaInstitute of Visual Neuroscience and Stem Cell Engineering, College of Life Sciences and Health, Wuhan University of Science and Technology, Wuhan, Hubei 430081, P.R. ChinaKey Laboratory of Molecular Biophysics of the Ministry of Education, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, Hubei 430074, P.R. ChinaKey Laboratory of Molecular Biophysics of the Ministry of Education, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, Hubei 430074, P.R. ChinaDepartment of Life Sciences, Glasgow Caledonian University, Glasgow, Scotland G4 0BA, UKKey Laboratory of Molecular Biophysics of the Ministry of Education, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, Hubei 430074, P.R. ChinaKey Laboratory of Molecular Biophysics of the Ministry of Education, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, Hubei 430074, P.R. ChinaKey Laboratory of Molecular Biophysics of the Ministry of Education, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, Hubei 430074, P.R. ChinaKey Laboratory of Molecular Biophysics of the Ministry of Education, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, Hubei 430074, P.R. ChinaKey Laboratory of Molecular Biophysics of the Ministry of Education, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, Hubei 430074, P.R. ChinaKey Laboratory of Molecular Biophysics of the Ministry of Education, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, Hubei 430074, P.R. ChinaKey Laboratory of Molecular Biophysics of the Ministry of Education, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, Hubei 430074, P.R. ChinaKey Laboratory of Molecular Biophysics of the Ministry of Education, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, Hubei 430074, P.R. ChinaKey Laboratory of Molecular Biophysics of the Ministry of Education, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, Hubei 430074, P.R. ChinaKey Laboratory of Molecular Biophysics of the Ministry of Education, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, Hubei 430074, P.R. ChinaDepartment of Life Sciences, Glasgow Caledonian University, Glasgow, Scotland G4 0BA, UKInstitute of Hydrobiology, Chinese Academy of Science, Wuhan 430072, P.R. China; Corresponding authorKey Laboratory of Molecular Biophysics of the Ministry of Education, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, Hubei 430074, P.R. China; Corresponding authorKey Laboratory of Molecular Biophysics of the Ministry of Education, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, Hubei 430074, P.R. China; Corresponding authorSummary: DEAH-Box Helicase 38 (DHX38) is a pre-mRNA splicing factor and also a disease-causing gene of autosomal recessive retinitis pigmentosa (arRP). The role of DHX38 in the development and maintenance of the retina remains largely unknown. In this study, by using the dhx38 knockout zebrafish model, we demonstrated that Dhx38 deficiency causes severe differentiation defects and apoptosis of retinal progenitor cells (RPCs) through disrupted mitosis and increased DNA damage. Furthermore, we found a significant accumulation of R-loops in the dhx38-deficient RPCs and human cell lines. Finally, we found that DNA replication stress is the prerequisite for R-loop-induced DNA damage in the DHX38 knockdown cells. Taken together, our study demonstrates a necessary role of DHX38 in the development of retina and reveals a DHX38/R-loop/replication stress/DNA damage regulatory axis that is relatively independent of the known functions of DHX38 in mitosis control.http://www.sciencedirect.com/science/article/pii/S2589004223021806Molecular physiologyDevelopmental genetics |
| spellingShingle | Kui Sun Yunqiao Han Jingzhen Li Shanshan Yu Yuwen Huang Yangjun Zhang Jamas Reilly Jiayi Tu Pan Gao Danna Jia Xiang Chen Hualei Hu Mengmeng Ren Pei Li Jiong Luo Xiang Ren Xianqin Zhang Xinhua Shu Fei Liu Mugen Liu Zhaohui Tang The splicing factor DHX38 enables retinal development through safeguarding genome integrity iScience Molecular physiology Developmental genetics |
| title | The splicing factor DHX38 enables retinal development through safeguarding genome integrity |
| title_full | The splicing factor DHX38 enables retinal development through safeguarding genome integrity |
| title_fullStr | The splicing factor DHX38 enables retinal development through safeguarding genome integrity |
| title_full_unstemmed | The splicing factor DHX38 enables retinal development through safeguarding genome integrity |
| title_short | The splicing factor DHX38 enables retinal development through safeguarding genome integrity |
| title_sort | splicing factor dhx38 enables retinal development through safeguarding genome integrity |
| topic | Molecular physiology Developmental genetics |
| url | http://www.sciencedirect.com/science/article/pii/S2589004223021806 |
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