Universität zu Köln

Boehm, Volker ORCID: 0000-0001-7588-9842, Kueckelmann, Sabrina ORCID: 0000-0001-8070-8823, Gerbracht, Jennifer, V, Kallabis, Sebastian ORCID: 0000-0003-1580-7109, Britto-Borges, Thiago, Altmueller, Janine, Krueger, Marcus, Dieterich, Christoph and Gehring, Niels H. (2021). SMG5-SMG7 authorize nonsense-mediated mRNA decay by enabling SMG6 endonucleolytic activity. Nat. Commun., 12 (1). BERLIN: NATURE PORTFOLIO. ISSN 2041-1723

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Abstract

Degradation of nonsense mediated mRNA decay (NMD) substrates is carried out by two seemingly independent pathways, SMG6-mediated endonucleolytic cleavage and/or SMG5-SMG7-induced accelerated deadenylation. Here the authors show that SMG5-SMG7 maintain NMD activity by permitting SMG6 activation. Eukaryotic gene expression is constantly controlled by the translation-coupled nonsense-mediated mRNA decay (NMD) pathway. Aberrant translation termination leads to NMD activation, resulting in phosphorylation of the central NMD factor UPF1 and robust clearance of NMD targets via two seemingly independent and redundant mRNA degradation branches. Here, we uncover that the loss of the first SMG5-SMG7-dependent pathway also inactivates the second SMG6-dependent branch, indicating an unexpected functional connection between the final NMD steps. Transcriptome-wide analyses of SMG5-SMG7-depleted cells confirm exhaustive NMD inhibition resulting in massive transcriptomic alterations. Intriguingly, we find that the functionally underestimated SMG5 can substitute the role of SMG7 and individually activate NMD. Furthermore, the presence of either SMG5 or SMG7 is sufficient to support SMG6-mediated endonucleolysis of NMD targets. Our data support an improved model for NMD execution that features two-factor authentication involving UPF1 phosphorylation and SMG5-SMG7 recruitment to access SMG6 activity.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Boehm, Volker UNSPECIFIED orcid.org/0000-0001-7588-9842 UNSPECIFIED Kueckelmann, Sabrina UNSPECIFIED orcid.org/0000-0001-8070-8823 UNSPECIFIED Gerbracht, Jennifer, V UNSPECIFIED UNSPECIFIED UNSPECIFIED Kallabis, Sebastian UNSPECIFIED orcid.org/0000-0003-1580-7109 UNSPECIFIED Britto-Borges, Thiago UNSPECIFIED UNSPECIFIED UNSPECIFIED Altmueller, Janine UNSPECIFIED UNSPECIFIED UNSPECIFIED Krueger, Marcus UNSPECIFIED UNSPECIFIED UNSPECIFIED Dieterich, Christoph UNSPECIFIED UNSPECIFIED UNSPECIFIED Gehring, Niels H. UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-583359
DOI:	10.1038/s41467-021-24046-3
Journal or Publication Title:	Nat. Commun.
Volume:	12
Number:	1
Date:	2021
Publisher:	NATURE PORTFOLIO
Place of Publication:	BERLIN
ISSN:	2041-1723
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language EXON-JUNCTION COMPLEX; UPF1 PHOSPHORYLATION; SURVEILLANCE COMPLEX; GLOBAL EXPRESSION; NMD; BINDING; IDENTIFICATION; DEGRADATION; QUANTIFICATION; TRANSLATION Multiple languages Multidisciplinary Sciences Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/58335