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

Authors :
Chen L
Wang Y
Lin J
Song Z
Wang Q
Zhao W
Wang Y
Xiu X
Deng Y
Li X
Li Q
Wang X
Li J
Liu X
Liu K
Zhou J
Li K
Liu Y
Liao S
Deng Q
Xu C
Sun Q
Wu S
Zhang K
Guan MX
Zhou T
Sun F
Cai X
Huang C
Shan G
Source :
Nature communications [Nat Commun] 2022 Oct 01; Vol. 13 (1), pp. 5769. Date of Electronic Publication: 2022 Oct 01.
Publication Year :
2022

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.<br /> (© 2022. The Author(s).)

Details

Language :
English
ISSN :
2041-1723
Volume :
13
Issue :
1
Database :
MEDLINE
Journal :
Nature communications
Publication Type :
Academic Journal
Accession number :
36182935
Full Text :
https://doi.org/10.1038/s41467-022-33356-z