Rapid UPF1 depletion illuminates the temporal dynamics of the NMD-regulated human transcriptome
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Abstract
The RNA helicase UPF1 shapes the transcriptome as the core factor of nonsense-mediated mRNA decay (NMD). The essential role of UPF1 in human cells has impeded efforts to delineate its directly regulated transcripts and molecular function. To investigate the effects of rapid UPF1 depletion, we engineered human cell lines with endogenous UPF1 fused to conditional degron tags. Temporal-resolution transcriptomic analyses identified direct target mRNAs, consisting predominantly of NMD substrates that are mostly stabilized within hours of UPF1 depletion. By integrating long-read sequencing and ribosome profiling data, we defined the consolidated NMD-regulated human transcriptome (NMDRHT), uncovering previously unannotated transcripts and establishing alternative splicing as a major contributor of NMD-targeted mRNAs. Additionally, we identified non-canonical NMD events that lack indication of being driven by other UPF1-dependent degradation routes. Our work refines the role of the post-transcriptional regulator UPF1 and introduces an experimentally validated NMD-regulated transcriptome as a navigable resource at https://nmdrht.uni-koeln.de.
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- Authors
- Boehm, V., Wallmeroth, D., Wulf, P. O., Popp, O., Teixeira Alves, L. G., Reinecke, L., Riedel, M., Wyler, E., Franitza, M., Becker, K., Polkovnychenko, K., Del Giudice, S., Benlasfer, N., Mertins, P., Landthaler, M., & Gehring, N. H.
- Affiliations
- University of Cologne (DE)
- Max Delbrück Center (DE)
- ORCID
- Venue
- Molecular Cell
- Publisher
- Elsevier BV
- Published
- 2025-09
- Volume
- 85
- Issue
- 18
- Pages
- 3524-3546.e12
- ISSN
- 1097-2765 (ISSN-L)
- OpenAlex
- W4414111375
- Cited by
- 23
- References
- 11
- Citations by year
- 2026: 19 · 2025: 3 · 2024: 1
- FWCI
- 6.64
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Molecular Cell (publishedVersion, cc-by)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Kölner Universitäts PublikationsServer (Universität zu Köln) (submittedVersion)
- MDC Repository (Max-Delbrueck-Center for Molecular Medicine) (submittedVersion)
- Funders
- University of Cologne Center for Molecular Medicine Cologne (C 05)
- MDC
- German Research Foundation (CRC1678, A08, INST 216/1321-1, GE 2014/4-1, LA 2941/6-1, GE 2014/6-2, GE 2014/13-1)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Research and Splicing
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA and protein synthesis mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA regulation and disease
- Keywords
- UPF1, nonsense-mediated mRNA decay, RNA helicase, mRNA stability, alternative splicing, post-transcriptional regulation, ribosome profiling, long-read sequencing, transcriptome annotation
- MeSH terms
- HeLa Cells, Humans, Ribosomes, RNA, Messenger, Trans-Activators, Alternative Splicing, RNA Helicases, HEK293 Cells, Nonsense Mediated mRNA Decay, Transcriptome
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