Readthrough of stop codons under limiting ABCE1 concentration involves frameshifting and inhibits nonsense-mediated mRNA decay

Annibaldis, Giuditta; Domanski, Michal; Dreos, René; Contu, Lara; Carl, Sarah; Kläy, Nina; Mühlemann, Oliver (2020). Readthrough of stop codons under limiting ABCE1 concentration involves frameshifting and inhibits nonsense-mediated mRNA decay. Nucleic acids research, 48(18), pp. 10259-10279. Oxford University Press 10.1093/nar/gkaa758

[img]
Preview
Text
Annibaldis_NAR2020_FRameshift-associated readthrough and NMD inhibition in ABCE1 KD.pdf - Published Version
Available under License Creative Commons: Attribution-Noncommercial (CC-BY-NC).

Download (5MB) | Preview

To gain insight into the mechanistic link between translation termination and nonsense-mediated mRNA decay (NMD), we depleted the ribosome recycling factor ABCE1 in human cells, resulting in an upregulation of NMD-sensitive mRNAs. Suppression of NMD on these mRNAs occurs prior to their SMG6-mediated endonucleolytic cleavage. ABCE1 depletion caused ribosome stalling at termination codons (TCs) and increased ribosome occupancy in 3' UTRs, implying enhanced TC readthrough. ABCE1 knockdown indeed increased the rate of readthrough and continuation of translation in different reading frames, providing a possible explanation for the observed NMD inhibition, since enhanced readthrough displaces NMD activating proteins from the 3' UTR. Our results indicate that stalling at TCs triggers ribosome collisions and activates ribosome quality control. Collectively, we show that improper translation termination can lead to readthrough of the TC, presumably due to ribosome collisions pushing the stalled ribosomes into the 3' UTR, where it can resume translation in-frame as well as out-of-frame.

Item Type:

Journal Article (Original Article)

Division/Institute:

08 Faculty of Science > Departement of Chemistry and Biochemistry
08 Faculty of Science > Departement of Chemistry and Biochemistry > NCCR RNA & Disease

Graduate School:

Graduate School for Cellular and Biomedical Sciences (GCB)

UniBE Contributor:

Annibaldis, Giuditta; Domanski, Michal; Contu, Lara and Mühlemann, Oliver

Subjects:

500 Science > 570 Life sciences; biology
500 Science > 540 Chemistry

ISSN:

0305-1048

Publisher:

Oxford University Press

Language:

English

Submitter:

Christina Schüpbach

Date Deposited:

18 Sep 2020 15:37

Last Modified:

09 Oct 2020 01:33

Publisher DOI:

10.1093/nar/gkaa758

BORIS DOI:

10.7892/boris.146588

URI:

https://boris.unibe.ch/id/eprint/146588

Actions (login required)

Edit item Edit item
Provide Feedback