Exportin 4 depletion leads to nuclear accumulation of a subset of circular RNAs

Liang Chen, Yucong Wang, Jiamei Lin, Zhenxing Song, Qinwei Wang, Wenfang Zhao, Yan Wang, Xiaoyu Xiu, Yuqi Deng, Xiuzhi Li, Qiqi Li, Xiaolin Wang, Jingxin Li, Xu Liu, Kunpeng Liu, Jincong Zhou, Kuan Li, Yuchan Liu, Shanhui Liao, Qin Deng, Chao Xu, Qianwen Sun, Shengzhou Wu, Kaiming Zhang, Min-Xin Guan, Tianhua Zhou, Fei Sun, Xiujun Cai, Chuan Huang () and Ge Shan ()
Additional contact information
Liang Chen: University of Science and Technology of China
Yucong Wang: University of Science and Technology of China
Jiamei Lin: Chongqing University
Zhenxing Song: Chongqing University
Qinwei Wang: University of Science and Technology of China
Wenfang Zhao: University of Science and Technology of China
Yan Wang: Wenzhou Medical University
Xiaoyu Xiu: Wenzhou Medical University
Yuqi Deng: University of Science and Technology of China
Xiuzhi Li: University of Science and Technology of China
Qiqi Li: University of Science and Technology of China
Xiaolin Wang: University of Science and Technology of China
Jingxin Li: University of Science and Technology of China
Xu Liu: University of Science and Technology of China
Kunpeng Liu: Tsinghua University
Jincong Zhou: Tsinghua University
Kuan Li: Tsinghua University
Yuchan Liu: University of Science and Technology of China
Shanhui Liao: University of Science and Technology of China
Qin Deng: Chongqing University
Chao Xu: University of Science and Technology of China
Qianwen Sun: Tsinghua University
Shengzhou Wu: Wenzhou Medical University
Kaiming Zhang: University of Science and Technology of China
Min-Xin Guan: Zhejiang University School of Medicine
Tianhua Zhou: Zhejiang University
Fei Sun: Zhejiang University School of Medicine
Xiujun Cai: Zhejiang University School of Medicine
Chuan Huang: Chongqing University
Ge Shan: University of Science and Technology of China

Nature Communications, 2022, vol. 13, issue 1, 1-18

Abstract: Abstract Numerous RNAs are exported from the nucleus, abnormalities of which lead to cellular complications and diseases. How thousands of circular RNAs (circRNAs) are exported from the nucleus remains elusive. Here, we provide lines of evidence to demonstrate a link between the conserved Exportin 4 (XPO4) and nuclear export of a subset of circRNAs in metazoans. Exonic circRNAs (ecircRNAs) with higher expression levels, larger length, and lower GC content are more sensitive to XPO4 deficiency. Cellular insufficiency of XPO4 leads to nuclear circRNA accumulation, circRNA:DNA (ciR-loop) formation, linear RNA:DNA (liR-loop) buildup, and DNA damage. DDX39 known to modulate circRNA export can resolve ciR-loop, and splicing factors involved in the biogenesis of circRNAs can also affect the levels of ciR-loop. Testis and brain are two organs with high abundance of circRNAs, and insufficient XPO4 levels are detrimental, as Xpo4 heterozygous mice display male infertility and neural phenotypes. Increased levels of ciR-loop, R-loop, and DNA damage along with decreased cell numbers are observed in testis and hippocampus of Xpo4 heterozygotes. This study sheds light on the understandings of mechanism of circRNA export and reveals the significance of efficient nuclear export of circRNAs in cellular physiology.

Date: 2022
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DOI: 10.1038/s41467-022-33356-z

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