The splicing factor DHX38 enables retinal development through safeguarding genome integrity

• Published in: iScience Vol. 26; no. 11; p. 108103
• Main Authors: Sun, Kui, Han, Yunqiao, Li, Jingzhen, Yu, Shanshan, Huang, Yuwen, Zhang, Yangjun, Reilly, Jamas, Tu, Jiayi, Gao, Pan, Jia, Danna, Chen, Xiang, Hu, Hualei, Ren, Mengmeng, Li, Pei, Luo, Jiong, Ren, Xiang, Zhang, Xianqin, Shu, Xinhua, Liu, Fei, Liu, Mugen, Tang, Zhaohui
• Format: Journal Article
• Language: English
• Published: Elsevier Inc 17-11-2023; Elsevier
• Subjects: Developmental genetics; Molecular physiology; Developmental genetics; Molecular physiology
• ISSN: 2589-0042; 2589-0042
• DOI: 10.1016/j.isci.2023.108103

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.
[Display omitted]
•Dhx38 is essential for RPCs survival and retinal development in zebrafish•Dhx38 deletion triggers R-loop-dependent genome instability in vivo and in vitro•Replication stress caused by R-loop accumulation is the main cause of DNA damage
Molecular physiology; Developmental genetics