A length-dependent evolutionarily conserved pathway controls nuclear export of circular RNAs.

Area of Science:

• Molecular Biology
• Genetics
• Cell Biology

Background:

• Circular RNAs (circRNAs) are prevalent RNA molecules derived from protein-coding genes.
• The precise mechanisms governing circRNA nuclear export and cytoplasmic accumulation are not fully understood.
• circRNA biogenesis and function are areas of intense research interest.

Purpose of the Study:

• To investigate the factors controlling circRNA localization and nuclear export.
• To identify specific proteins involved in regulating circRNA transport.
• To determine if circRNA length influences its nuclear export pathway.

Main Methods:

• RNA interference (RNAi) screening in *Drosophila* to identify key regulatory proteins.
• Analysis of circRNA localization in cells upon depletion of specific helicase proteins.
• Comparative studies using human cell lines and homologs of *Drosophila* proteins.

Main Results:

• Depletion of *Drosophila* Hel25E leads to nuclear accumulation of long circRNAs (>800 nucleotides) but not short ones.
• Human homologs UAP56 and URH49 show differential regulation of circRNA localization based on length.
• UAP56 depletion enriches long circRNAs in the nucleus, while URH49 depletion enriches short circRNAs.

Conclusions:

• CircRNA length is a critical determinant for nuclear export pathway selection.
• Helicase proteins, including Hel25E, UAP56, and URH49, play conserved roles in regulating circRNA localization.
• These findings reveal a length-dependent mechanism for circRNA nuclear export.