Cancer-associated snaR-A noncoding RNA interacts with core splicing machinery and disrupts processing of mRNA subpopulations

Sihang Zhou, Simon Lizarazo, Sandip Chorghade, Leela Mouli, Ruiying Cheng, Rajendra K C, Auinash Kalsotra and Kevin Van Bortle ()
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Sihang Zhou: University of Illinois Urbana-Champaign, Department of Cell and Developmental Biology
Simon Lizarazo: University of Illinois Urbana-Champaign, Department of Molecular and Integrative Physiology
Sandip Chorghade: University of Illinois Urbana-Champaign, Department of Biochemistry
Leela Mouli: University of Illinois Urbana-Champaign, School of Molecular and Cellular Biology
Ruiying Cheng: University of Illinois Urbana-Champaign, Department of Cell and Developmental Biology
Rajendra K C: University of Illinois Urbana-Champaign, Center for Biophysics and Quantitative Biology
Auinash Kalsotra: University of Illinois Urbana-Champaign, Department of Biochemistry
Kevin Van Bortle: University of Illinois Urbana-Champaign, Department of Cell and Developmental Biology

Nature Communications, 2025, vol. 16, issue 1, 1-15

Abstract: Abstract Expansion of RNA polymerase III (Pol III) activity in cancer can activate the transcription of typically silent small RNA genes, including snaR-A (small NF90-associated RNA isoform A), a hominid-specific noncoding RNA that promotes cell proliferation through unclear mechanisms. Here, we show that snaR-A interacts with mRNA splicing factors, including the U2 small nuclear ribonucleoprotein (snRNP) subunit SF3B2, and localizes near subnuclear foci enriched in splicing machinery. Overexpression of snaR-A increases intron retention, a hallmark of inefficient splicing, whereas its depletion enhances splicing of mRNAs characterized by high U2 snRNP occupancy and nuclear speckle proximity. These improvements in splicing coincide with reduced cell proliferation, consistent with tumor-level patterns linking snaR-A to growth in primary cancers. Together, these findings identify snaR-A as a molecular antagonist of splicing and potential disease driver in cancer. We propose that snaR-A-related splicing perturbation may phenocopy splicing defects attributed to U2 snRNP mutations in cancer, eliciting an alternative, non-mutational mechanism of splicing dysregulation during tumorigenesis.

Date: 2025
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DOI: 10.1038/s41467-025-65448-x

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