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PreprintCited by 23RNA Research and SplicingRNA and protein synthesis mechanismsRNA regulation and disease

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Rapid UPF1 depletion illuminates the temporal dynamics of the NMD-regulated transcriptome in human cells

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Boehm, Volker, Wallmeroth, Damaris, Wulf, Paul O., Alves, Luiz Gustavo Teixeira, Popp, Oliver, Riedel, Maximilian, Wyler, Emanuel, Franitza, Marek, Gerbracht, Jennifer V., Becker, Kerstin, Polkovnychenko, Karina, Del Giudice, Simone, Benlasfer, Nouhad, Mertins, Philipp, Landthaler, Markus, Gehring, Niels H.·2024·Molecular Cell
DOI 10.1101/2024.03.04.583328

Preprint — published as 10.1016/j.molcel.2025.08.015 · Paper page

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Abstract

The helicase UPF1 acts as the central essential factor in human nonsense-mediated mRNA decay (NMD) and is involved in various other mRNA degradation processes. Given its multifunctionality, distinguishing between mRNAs regulated directly and indirectly by UPF1 remains a critical challenge. We engineered two different conditional degron tags into endogenous UPF1 in human cell lines to probe the consequences of UPF1 rapid depletion. UPF1 degradation inhibits NMD within hours and strongly stabilizes endogenous NMD substrates, which can be classified into different groups based on their expression kinetics. Extended UPF1 depletion results in massive transcript and isoform alterations, partially driven by secondary effects. We define a high-confidence UPF1-regulated core set of transcripts, which consists mostly of NMD substrates. NMD-regulated genes are involved in brain development and the integrated stress response, among other biological processes. In summary, UPF1 degron systems rapidly inhibit NMD, providing valuable insights into its roles across various experimental systems.

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Metadata

Authors
Boehm, V., Wallmeroth, D., Wulf, P. O., Alves, L. G. T., Popp, O., Riedel, M., Wyler, E., Franitza, M., Gerbracht, J. V., 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)
Corresponding author
  • Landthaler, Markus
  • Gehring, Niels H.
ORCID
Venue
Molecular Cell
Publisher
openRxiv
Published
2024-03-08
Volume
85
Issue
18
Pages
3524-3546.e12
ISSN
1097-2765 (ISSN-L)
DOI
10.1101/2024.03.04.583328
OpenAlex
W4414111375
Cited by
23
References
2
Citations by year
2026: 19 · 2025: 3 · 2024: 1
FWCI
6.57
Type
journal article
Language
en
Open access
Licence
cc-by
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
  • MDC
  • Deutsche Forschungsgemeinschaft (GE2014/6-2, CRC 1678, GE 2014/13‐1, GE 2014/4-1, INST 216/1321-1, LA 2941/6-1)
  • Center for Molecular Medicine Cologne, University of Cologne
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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