iScience (Nov 2023)
The splicing factor DHX38 enables retinal development through safeguarding genome integrity
- 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
Affiliations
- Kui Sun
- Key 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
- Yunqiao Han
- Key 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
- Jingzhen Li
- Research Center for Biochemistry and Molecular Biology, Jiangsu Key Laboratory of Brain Disease Bioinformation, Xuzhou Medical University, Xuzhou, Jiangsu 221004, P.R. China
- Shanshan Yu
- Institute of Visual Neuroscience and Stem Cell Engineering, College of Life Sciences and Health, Wuhan University of Science and Technology, Wuhan, Hubei 430081, P.R. China
- Yuwen Huang
- Key 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
- Yangjun Zhang
- Key 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
- Jamas Reilly
- Department of Life Sciences, Glasgow Caledonian University, Glasgow, Scotland G4 0BA, UK
- Jiayi Tu
- Key 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
- Pan Gao
- Key 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
- Danna Jia
- Key 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
- Xiang Chen
- Key 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
- Hualei Hu
- Key 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
- Mengmeng Ren
- Key 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
- Pei Li
- Key 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
- Jiong Luo
- Key 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
- Xiang Ren
- Key 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
- Xianqin Zhang
- Key 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
- Xinhua Shu
- Department of Life Sciences, Glasgow Caledonian University, Glasgow, Scotland G4 0BA, UK
- Fei Liu
- Institute of Hydrobiology, Chinese Academy of Science, Wuhan 430072, P.R. China; Corresponding author
- Mugen Liu
- Key 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 author
- Zhaohui Tang
- Key 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 author
- Journal volume & issue
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Vol. 26,
no. 11
p. 108103
Abstract
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.
