DFG
Deutsche Forschungsgemeinschaft
Gehring Lab | RNA Biology
Welcome to the Gehring Lab at the University of Cologne.
We investigate how human genes are correctly expressed and regulated on the RNA level.
Learn more about our team and research below.
Learn moreOverview
Overview
Overview
Mechanistic understanding of human gene expression regulation
Gene expression is the fundamental cellular process that uses the genomic information in our DNA to synthesize gene products. We focus on understanding the general mechanisms and processes that regulate gene expression and thereby ensure faithful protein production. Specifically, we are interested how ribonucleoprotein (RNP) complexes influence various stages of the messenger RNA (mRNA) lifecycle. More detailed information about ongoing research projects in the lab can be found below.
Nonsense-mediated mRNA decay (NMD)
We study the molecular mechanism how unproductive mRNAs are detected and removed by the NMD pathway, which serves quality control and regulatory functions in human cells.
NMD - Overview
NMD - Details
To maintain the correct production of functional proteins in the cell, quality control mechanisms constantly monitor each step of gene expression. We are particularly interested in the nonsense-mediated mRNA decay pathway (NMD), a translation-coupled surveillance mechanism. Random mistakes, genomic mutations or alternative splicing are causes in human cells that lead to mRNA transcripts containing premature translation termination codon (PTC). Translation of those unproductive or defective mRNAs would lead to unfunctional or potentially toxic proteins and are frequently the cause for human diseases. As a quality control and regulatory mechanism, NMD detects and degrades PTC-containing mRNAs, thereby keeping the cellular transcriptome clean.
We use various experimental approaches in cultured human cells including high-throughput methods to dissect and unravel the complex NMD mechanism. We are particularly interested to understand the molecular choreography involving multiple NMD factors with still unclear functions, which ultimately result in accurate detection of PTC-containing transcripts and their endonucleolytic cleavage.
Exon junction complex (EJC)
We study how and which processes are regulated by the EJC, a multi-protein complex that is deposited by the splicing process on mRNAs and influences the fate of the transcript via multiple adapter proteins.
EJC - Overview
EJC - Details
From the moment when a new mRNA is transcribed by the RNA polymerase, RNA-binding proteins associate with this transcript and influence its fate. One protein complex in particular, called the exon junction complex (EJC), is deposited on the mRNA during splicing. The EJC remains bound on the mRNA until it is usually displaced in the cytoplasm by translating ribosomes. Until then, the EJC regulates virtually all steps of mRNA biology, including transcription, alternative splicing, nuclear mRNA export, translation and ultimately, the EJC is involved in quality control (see nonsense-mediated mRNA decay).
We study the biological role and mechanistic function of the EJC, which often involves peripheral EJC factors that are dynamically recruited to influence particular steps of the mRNA lifecycle. We employ a combination of molecular biology, genetics and biochemistry approaches to study the EJC in cultured human cells.
Latest findings on our research topics can be found in our HIGHLIGHTS or PUBLICATION section below.
Niels H. Gehring
Professor, Principal Investigator
Frau Rosenfeld
Secretary
Juliane Hancke
Technician
Dr. Volker Böhm
Staff Scientist
André Müller
PhD student
Sophie Theunissen
PhD student
Silke Modersohn
Technician
Franz Reichel
PhD student
Fenja Meyer zu Altenschildesche
Technician
Dominik Requate
PhD student
2026
A targetable dependency on nonsense-mediated decay for cellular homeostasis and immune control in small cell lung cancer
Torres-Fernández LA, Boehm V, Kaufmann J, Becker JP, Garcia-Marquez M, de Bruijn B, Rumińska A, Müller C, Bosco G, Alavinejad N, Lovric L, Bihler JI, Schulte H, Davoodi P, Schöllhorn A, Weihrauch KR, Kaiser L, Ibruli O, Liu F, Androulidaki A, Wobst N, Schmiel M, Valiulis J, Maas L, D'Rozario J, Sakthivelu V, Göbel B, Touet M, Brägelmann J, Höpker K, John F, Wolf J, Knapp S, Quaas A, Cartolano M, von Karstedt S, Beleggia F, Rammensee HG, Gouttefangeas C, Schlößer HA, Riemer AB, Reinhardt HC, Gehring NH, Peifer M, Thomas RK, George J.
Mol Cancer. 2026 Aug 27;25(1):210. doi: 10.1186/s12943-026-02750-2.
Details
Abstract
Small cell lung cancer (SCLC) is one of the most aggressive malignancies, characterized by rapid metastatic dissemination and poor overall survival. Despite harboring excessive alterations, expectedly resulting in immunogenic neoantigens, patients with SCLC remain largely refractory to immunotherapy. We found abundant frameshift mutations in SCLC, regarded as highly immunogenic, counterbalanced by a hyperactive nonsense-mediated decay (NMD) pathway, responsible for frameshift-mRNA degradation. NMD activity correlated with tumor mutational burden (TMB) across cancers, suggesting that SCLC and other TMBhigh cancers may depend on NMD to limit the accumulation of mutation-derived byproducts in order to maintain cellular homeostasis and evade immune recognition. In TMBhigh SCLC models, inhibition of NMD impaired cell proliferation and induced ER stress-dependent apoptosis due to the accumulation of misfolded proteins. Genetic and pharmacological NMD inhibition in vivo effectively controlled TMBhigh tumor growth without overt toxicity. By integrating genome and transcriptome sequencing with MHC-I immunopeptidomics and functional in vitro and in vivo assays, we identified that NMD inhibition boosted neoantigen expression and presentation by tumor cells and increased T cell recognition, thus enhancing overall tumor immunogenicity and further improving immunotherapy efficacy in vivo. Our work shows that SCLC - as a TMBhigh cancer - relies on NMD for survival and immune escape, uncovering a novel TMB-dependent tractable vulnerability for this devastating disease.
PubMed
SMG1:SMG8:SMG9-complex integrity supports efficient execution of nonsense-mediated mRNA decay
Kueckelmann S, Theunissen S, Meyer Zu Altenschildesche F, von Ondarza L, Lackmann JW, Franitza M, Becker K, Boehm V, Gehring NH.
Nucleic Acids Res. 2026 Feb 24;54(5):gkag193. doi: 10.1093/nar/gkag193.
Details
Abstract
Nonsense-mediated mRNA decay (NMD) is a translation-dependent mRNA turnover pathway, which degrades transcripts containing premature termination codons. NMD activation depends on phosphorylation of the RNA helicase UPF1 by the SMG1 kinase, which acts in a complex with SMG8 and SMG9. Structural and biochemical studies have implicated SMG8 and SMG9 as regulators of SMG1 activity, but their contributions to NMD in human cells remain incompletely defined. Here, we systematically dissect the roles of SMG8 and SMG9 in NMD using genetic and pharmacological perturbations in multiple human cell lines. Deletion of the kinase inhibitory domain (KID) of SMG8 did not affect UPF1 phosphorylation or NMD efficiency, demonstrating that this domain is dispensable in vivo. Complete loss of SMG8 or SMG9 resulted in only modest NMD impairment and was accompanied by moderately increased UPF1 phosphorylation. However, SMG8- or SMG9-deficient cells exhibited pronounced hypersensitivity to partial pharmacological inhibition of SMG1, leading to synergistic, transcriptome-wide stabilization of NMD targets. These effects were reproducible across different cellular contexts, underscoring a general regulatory role for SMG8 and SMG9. Together, our results establish SMG8 and SMG9 as nonessential modulators that safeguard the efficiency and perturbation tolerance of the NMD pathway in human cells.
PubMed
Composite SMG5-SMG6 PIN domain formation is essential for NMD
Kurscheidt K, Theunissen S, Pasquali N, Becker K, Boehm V, Conti E, Gehring NH.
Nat Commun. 2026 Feb 19;17(1):1934. doi: 10.1038/s41467-026-69819-w.
Details
Abstract
Nonsense-mediated mRNA decay (NMD) relies on the coordinated assembly and action of multiple protein factors. Degradation of target mRNAs begins with endonucleolytic cleavage near premature stop codons, but the mechanisms of endonuclease activation and regulation remain unclear. Using structural predictions, biochemical in vitro assays, and cell-based NMD analysis, we show that SMG5 and SMG6 interact via their PIN domains to form a composite interface (cPIN) with full endonuclease activity. In vitro reconstituted SMG5-SMG6 cPIN heterodimers show high activity, as SMG5 completes the SMG6 active site and substrate binding site. Mutations in residues at their predicted interaction surfaces, RNA-binding sites, or active-site attenuate or abolish cPIN activity in vitro and impair cellular NMD. Our findings demonstrate how paralogous PIN domains complement each other to assemble a highly active endonuclease in NMD, providing a structural and mechanistic explanation for efficient NMD substrate degradation.
PubMed
2025
Rapid UPF1 depletion illuminates the temporal dynamics of the NMD-regulated human transcriptome
Boehm V, Wallmeroth D, Wulf PO, Popp O, Teixeira Alves LG, Reinecke L, Riedel M, Wyler E, Franitza M, Becker K, Polkovnychenko K, Del Giudice S, Benlasfer N, Mertins P, Landthaler M, Gehring NH.
Mol Cell. 2025 Sep 18;85(18):3524-3546.e12. doi: 10.1016/j.molcel.2025.08.015. Epub 2025 Sep 10.
Details
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.
PubMed
NMDRHT resource
CRC1678
Collaborative Research Center 1678
University of Cologne
Sustainability Office
of the University of Cologne
Opportunities for Bachelor and Master Theses & Project and Lab Modules
Please send inquiries for Bachelor and Master theses or laboratory modules to Niels Gehring
You can find us on the third floor (OG3) of building number 301 (Molekulare Biowissenschaften), located at:
Zülpicher Str. 47a | 50674 Cologne