Universität zu Köln

Boehm, Volker ORCID: 0000-0001-7588-9842, Wallmeroth, Damaris ORCID: 0000-0003-3437-4070, Wulf, Paul O., Popp, Oliver, Teixeira Alves, Luiz Gustavo, Reinecke, Lucie, Riedel, Maximilian, Wyler, Emanuel, Franitza, Marek, Becker, Kerstin ORCID: 0009-0009-7897-7181, Polkovnychenko, Karina ORCID: 0009-0001-9468-3150, Del Giudice, Simone, Benlasfer, Nouhad, Mertins, Philipp, Landthaler, Markus and Gehring, Niels H. ORCID: 0000-0001-7792-1164 (2025). Rapid UPF1 depletion illuminates the temporal dynamics of the NMD-regulated human transcriptome. Molecular Cell, 85 (18). 3524-3546.e12. Elsevier. ISSN 1097-2765

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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 tran- scripts 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 tran- scripts 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 degra- dation routes. Our work refines the role of the post-transcriptional regulator UPF1 and introduces an exper- imentally validated NMD-regulated transcriptome as a navigable resource at https://nmdrht.uni-koeln.de.

Item Type:	Article
Creators:	Creators Email ORCID ORCID Put Code Boehm, Volker UNSPECIFIED https://orcid.org/0000-0001-7588-9842 UNSPECIFIED Wallmeroth, Damaris UNSPECIFIED https://orcid.org/0000-0003-3437-4070 UNSPECIFIED Wulf, Paul O. UNSPECIFIED UNSPECIFIED UNSPECIFIED Popp, Oliver UNSPECIFIED UNSPECIFIED UNSPECIFIED Teixeira Alves, Luiz Gustavo UNSPECIFIED UNSPECIFIED UNSPECIFIED Reinecke, Lucie UNSPECIFIED UNSPECIFIED UNSPECIFIED Riedel, Maximilian UNSPECIFIED UNSPECIFIED UNSPECIFIED Wyler, Emanuel UNSPECIFIED UNSPECIFIED UNSPECIFIED Franitza, Marek UNSPECIFIED UNSPECIFIED UNSPECIFIED Becker, Kerstin UNSPECIFIED https://orcid.org/0009-0009-7897-7181 UNSPECIFIED Polkovnychenko, Karina UNSPECIFIED https://orcid.org/0009-0001-9468-3150 UNSPECIFIED Del Giudice, Simone UNSPECIFIED UNSPECIFIED UNSPECIFIED Benlasfer, Nouhad UNSPECIFIED UNSPECIFIED UNSPECIFIED Mertins, Philipp UNSPECIFIED UNSPECIFIED UNSPECIFIED Landthaler, Markus UNSPECIFIED UNSPECIFIED UNSPECIFIED Gehring, Niels H. UNSPECIFIED https://orcid.org/0000-0001-7792-1164 UNSPECIFIED
URN:	urn:nbn:de:hbz:38-809250
Identification Number:	10.1016/j.molcel.2025.08.015
Journal or Publication Title:	Molecular Cell
Volume:	85
Number:	18
Page Range:	3524-3546.e12
Number of Pages:	36
Date:	18 September 2025
Publisher:	Elsevier
ISSN:	1097-2765
Language:	English
Faculty:	Faculty of Mathematics and Natural Sciences
Divisions:	Cologne Center for Genomics Faculty of Mathematics and Natural Sciences > Department of Biology > Institute for Genetics Zentrum für Molekulare Medizin
Subjects:	Medical sciences Medicine
['eprint_fieldname_oa_funders' not defined]:	Publikationsfonds UzK
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/80925