Aspartyl-tRNA synthetase 2 orchestrates iron-sulfur metabolism in hematopoietic stem cells via fine-tuning alternative RNA splicing
Year: 2023
Type: article
Abstract: ). The role of Dars2 in the self-renewal and differentiation of hematopoietic stem cells (HSCs) is unknown. Here, we show that knockout (KO) of Dars2 significantly impairs the maintenance of hematopoietic stem and progenitor cells (HSPCs) without involving its tRNA synthetase activity. Dars2 KO results in significantly reduced expression of Srsf2/3/6 and impairs multiple events of mRNA alternative splicing (AS). Dars2 directly localizes to Srsf3-labeled spliceosomes in HSPCs and regulates the stability of Srsf3. Dars2-deficient HSPCs exhibit aberrant AS of mTOR and Slc22a17. Dars2 KO greatly suppresses the levels of labile ferrous iron and iron-sulfur cluster-containing proteins, which dampens mitochondrial metabolic activity and DNA damage repair pathways in HSPCs. Our study reveals that Dars2 plays a crucial role in the iron-sulfur metabolism and maintenance of HSPCs by modulating RNA splicing.
Source: Cell Reports
Language: English
Topic: RNA Research and Splicing
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $5,460
Funders: Innovative Research Team of High-level Local University in Shanghai, National Natural Science Foundation of China, Ministry of Science and Technology of the People's Republic of China, Shanxi Scholarship Council of China, Science and Technology Commission of Shanghai Municipality, Recruitment Program of Global Experts, ShanXi Science and Technology Department, Department of Human Resources and Social Security of Shanxi Province, School of Medicine, Shanghai Jiao Tong University, Major Research Plan, National Key Research and Development Program of China
OpenAlex ID: W4387610786