Universität zu Köln

Wallmeroth, Damaris ORCID: 0000-0003-3437-4070, Lackmann, Jan-Wilm ORCID: 0000-0001-8182-8034, Kueckelmann, Sabrina ORCID: 0000-0001-8070-8823, Altmueller, Janine, Dieterich, Christoph ORCID: 0000-0001-9468-6311, Boehm, Volker ORCID: 0000-0001-7588-9842 and Gehring, Niels H. (2022). Human UPF3A and UPF3B enable fault-tolerant activation of nonsense-mediated mRNA decay. Embo J., 41 (10). HOBOKEN: WILEY. ISSN 1460-2075

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Abstract

The paralogous human proteins UPF3A and UPF3B are involved in recognizing mRNAs targeted by nonsense-mediated mRNA decay (NMD). UPF3B has been demonstrated to support NMD, presumably by bridging an exon junction complex (EJC) to the NMD factor UPF2. The role of UPF3A has been described either as a weak NMD activator or an NMD inhibitor. Here, we present a comprehensive functional analysis of UPF3A and UPF3B in human cells using combinatory experimental approaches. Overexpression or knockout of UPF3A as well as knockout of UPF3B did not substantially change global NMD activity. In contrast, the co-depletion of UPF3A and UPF3B resulted in a marked NMD inhibition and a transcriptome-wide upregulation of NMD substrates, demonstrating a functional redundancy between both NMD factors. In rescue experiments, UPF2 or EJC binding-deficient UPF3B largely retained NMD activity. However, combinations of different mutants, including deletion of the middle domain, showed additive or synergistic effects and therefore failed to maintain NMD. Collectively, UPF3A and UPF3B emerge as fault-tolerant, functionally redundant NMD activators in human cells.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Wallmeroth, Damaris UNSPECIFIED orcid.org/0000-0003-3437-4070 UNSPECIFIED Lackmann, Jan-Wilm UNSPECIFIED orcid.org/0000-0001-8182-8034 UNSPECIFIED Kueckelmann, Sabrina UNSPECIFIED orcid.org/0000-0001-8070-8823 UNSPECIFIED Altmueller, Janine UNSPECIFIED UNSPECIFIED UNSPECIFIED Dieterich, Christoph UNSPECIFIED orcid.org/0000-0001-9468-6311 UNSPECIFIED Boehm, Volker UNSPECIFIED orcid.org/0000-0001-7588-9842 UNSPECIFIED Gehring, Niels H. UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-688310
DOI:	10.15252/embj.2021109191
Journal or Publication Title:	Embo J.
Volume:	41
Number:	10
Date:	2022
Publisher:	WILEY
Place of Publication:	HOBOKEN
ISSN:	1460-2075
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language EXON JUNCTION COMPLEX; FREE QUANTIFICATION; NMD; TRANSLATION; BINDING; PROTEIN; GENE; IDENTIFICATION; EXPRESSION; CELLS Multiple languages Biochemistry & Molecular Biology; Cell Biology Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/68831