A nuclear RNA degradation code is recognized by PAXT for eukaryotic transcriptome surveillance

Lindsey V Soles¹, Liang Liu¹, Xudong Zou², Yoseop Yoon¹, Shuangyu Li¹, Lusong Tian¹, Marielle Valdez¹, Angela M Yu³, Hong Yin⁴, Wei Li⁵, Fangyuan Ding⁶, Georg Seelig⁷, Lei Li², Yongsheng Shi⁸

Affiliations

¹ Department of Microbiology and Molecular Genetics, School of Medicine, University of California, Irvine, Irvine, CA 92617, USA.
² Institute of Systems and Physical Biology, Shenzhen Bay Laboratory, Shenzhen 518107, China.
³ Therapeutic Innovation Center (THINC), and Verna and Marrs McLean Department of Biochemistry and Molecular Pharmacology, Baylor College of Medicine, Houston, TX, USA.
⁴ Department of Biomedical Engineering, University of California, Irvine, Irvine, CA 92617, USA.
⁵ Department of Biological Chemistry, University of California, Irvine, Irvine, CA 92617, USA; The Center for RNA Science and Therapeutics, University of California, Irvine, Irvine, CA 92697, USA.
⁶ Department of Biomedical Engineering, University of California, Irvine, Irvine, CA 92617, USA; The Center for RNA Science and Therapeutics, University of California, Irvine, Irvine, CA 92697, USA.
⁷ Department of Electrical and Computer Engineering, University of Washington, Seattle, Seattle, WA 98195, USA.
⁸ Department of Microbiology and Molecular Genetics, School of Medicine, University of California, Irvine, Irvine, CA 92617, USA; The Center for RNA Science and Therapeutics, University of California, Irvine, Irvine, CA 92697, USA. Electronic address: yongshes@uci.edu.

PMID: 40187348
PMCID: PMC12010247 (available on 2026-04-17)
DOI: 10.1016/j.molcel.2025.03.010

A nuclear RNA degradation code is recognized by PAXT for eukaryotic transcriptome surveillance

Lindsey V Soles et al. Mol Cell. 2025.

. 2025 Apr 17;85(8):1575-1588.e9.

doi: 10.1016/j.molcel.2025.03.010. Epub 2025 Apr 4.

Authors

Affiliations

¹ Department of Microbiology and Molecular Genetics, School of Medicine, University of California, Irvine, Irvine, CA 92617, USA.
² Institute of Systems and Physical Biology, Shenzhen Bay Laboratory, Shenzhen 518107, China.
³ Therapeutic Innovation Center (THINC), and Verna and Marrs McLean Department of Biochemistry and Molecular Pharmacology, Baylor College of Medicine, Houston, TX, USA.
⁴ Department of Biomedical Engineering, University of California, Irvine, Irvine, CA 92617, USA.
⁵ Department of Biological Chemistry, University of California, Irvine, Irvine, CA 92617, USA; The Center for RNA Science and Therapeutics, University of California, Irvine, Irvine, CA 92697, USA.
⁶ Department of Biomedical Engineering, University of California, Irvine, Irvine, CA 92617, USA; The Center for RNA Science and Therapeutics, University of California, Irvine, Irvine, CA 92697, USA.
⁷ Department of Electrical and Computer Engineering, University of Washington, Seattle, Seattle, WA 98195, USA.
⁸ Department of Microbiology and Molecular Genetics, School of Medicine, University of California, Irvine, Irvine, CA 92617, USA; The Center for RNA Science and Therapeutics, University of California, Irvine, Irvine, CA 92697, USA. Electronic address: yongshes@uci.edu.

PMID: 40187348
PMCID: PMC12010247 (available on 2026-04-17)
DOI: 10.1016/j.molcel.2025.03.010

Abstract

The RNA exosome plays critical roles in eukaryotic RNA degradation, but how it specifically recognizes its targets remains unclear. The poly(A) tail exosome targeting (PAXT) connection is a nuclear adaptor that recruits the exosome to polyadenylated RNAs, especially transcripts polyadenylated at intronic poly(A) sites. Here, we show that PAXT-mediated RNA degradation is induced by the combination of a 5' splice site (ss) and a poly(A) junction (PAJ) but not by either sequence alone. These sequences are bound by U1 small nuclear ribonucleoprotein particle (snRNP) and cleavage/polyadenylation factors, which, in turn, cooperatively recruit PAXT. As the 5' ss-PAJ combination is typically absent on correctly processed RNAs, it functions as a "nuclear RNA degradation code" (NRDC). Importantly, disease-associated single nucleotide polymorphisms that create novel 5' ss in 3' untranslated regions can induce aberrant mRNA degradation via the NRDC mechanism. Together, our study identified the first NRDC, revealed its recognition mechanism, and characterized its role in human diseases.

Keywords: RNA degradation; RNA exosome; RNA surveillance; cleavage and polyadenylation; gene expression; intronic polyadenylation; pre-mRNA 3′ processing; pre-mRNA splicing; quality control.

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Conflict of interest statement

Declaration of interests The authors declare no competing interests.

Update of

A nuclear RNA degradation code for eukaryotic transcriptome surveillance.
Soles LV, Liu L, Zou X, Yoon Y, Li S, Tian L, Valdez MC, Yu A, Yin H, Li W, Ding F, Seelig G, Li L, Shi Y. Soles LV, et al. bioRxiv [Preprint]. 2024 Jul 24:2024.07.23.604837. doi: 10.1101/2024.07.23.604837. bioRxiv. 2024. Update in: Mol Cell. 2025 Apr 17;85(8):1575-1588.e9. doi: 10.1016/j.molcel.2025.03.010. PMID: 39211185 Free PMC article. Updated. Preprint.

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A nuclear RNA degradation code is recognized by PAXT for eukaryotic transcriptome surveillance

Affiliations

A nuclear RNA degradation code is recognized by PAXT for eukaryotic transcriptome surveillance

Authors

Affiliations

Abstract

Conflict of interest statement

Update of

References

MeSH terms

Substances

Grants and funding

LinkOut - more resources

Full Text Sources

Research Materials