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The splicing factor DHX38 enables retinal development through safeguarding genome integrity
Kui Sun1, Yunqiao Han1, Jingzhen Li2
1Key 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.
Iscience
|October 23, 2023
Summary
DEAH-Box Helicase 38 (DHX38) is crucial for retinal development. Its deficiency causes retinal progenitor cell defects and apoptosis via R-loop accumulation and DNA damage, independent of its known splicing role.
Area of Science:
- Molecular Biology
- Genetics
- Developmental Biology
Background:
- DEAH-Box Helicase 38 (DHX38) is a pre-mRNA splicing factor implicated in autosomal recessive retinitis pigmentosa (arRP).
- The specific role of DHX38 in retinal development and maintenance is not well understood.
Purpose of the Study:
- To investigate the function of DHX38 in retinal development using a zebrafish model.
- To elucidate the molecular mechanisms underlying retinal defects caused by DHX38 deficiency.
Main Methods:
- Utilized a dhx38 knockout zebrafish model.
- Analyzed retinal progenitor cell (RPC) differentiation, apoptosis, mitosis, and DNA damage.
- Investigated R-loop accumulation in RPCs and human cell lines.
- Assessed the role of DNA replication stress in DHX38 knockdown cells.
Main Results:
- Dhx38 deficiency led to severe differentiation defects and apoptosis in RPCs.
- Mitotic disruption and increased DNA damage were observed in Dhx38-deficient retinas.
- Significant R-loop accumulation occurred in DHX38-deficient RPCs and human cell lines.
- DNA replication stress was identified as a prerequisite for R-loop-induced DNA damage in DHX38 knockdown cells.
Conclusions:
- DHX38 plays a vital role in retinal development.
- A novel DHX38/R-loop/replication stress/DNA damage regulatory axis was revealed, impacting retinal progenitor cells.
- This axis appears to operate independently of DHX38's known functions in mitosis control.
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