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Autoregulation of the nonsense-mediated mRNA decay pathway in human cells


Yepiskoposyan, H; Aeschimann, F; Nilsson, D; Okoniewski, M; Mühlemann, O (2011). Autoregulation of the nonsense-mediated mRNA decay pathway in human cells. RNA, 17(12):2108-2118.

Abstract

Nonsense-mediated mRNA decay (NMD) is traditionally portrayed as a quality-control mechanism that degrades mRNAs with truncated open reading frames (ORFs). However, it is meanwhile clear that NMD also contributes to the post-transcriptional gene regulation of numerous physiological mRNAs. To identify endogenous NMD substrate mRNAs and analyze the features that render them sensitive to NMD, we performed transcriptome profiling of human cells depleted of the NMD factors UPF1, SMG6, or SMG7. It revealed that mRNAs up-regulated by NMD abrogation had a greater median 3'-UTR length compared with that of the human mRNAome and were also enriched for 3'-UTR introns and uORFs. Intriguingly, most mRNAs coding for NMD factors were among the NMD-sensitive transcripts, implying that the NMD process is autoregulated. These mRNAs all possess long 3' UTRs, and some of them harbor uORFs. Using reporter gene assays, we demonstrated that the long 3' UTRs of UPF1, SMG5, and SMG7 mRNAs are the main NMD-inducing features of these mRNAs, suggesting that long 3' UTRs might be a frequent trigger of NMD.

Nonsense-mediated mRNA decay (NMD) is traditionally portrayed as a quality-control mechanism that degrades mRNAs with truncated open reading frames (ORFs). However, it is meanwhile clear that NMD also contributes to the post-transcriptional gene regulation of numerous physiological mRNAs. To identify endogenous NMD substrate mRNAs and analyze the features that render them sensitive to NMD, we performed transcriptome profiling of human cells depleted of the NMD factors UPF1, SMG6, or SMG7. It revealed that mRNAs up-regulated by NMD abrogation had a greater median 3'-UTR length compared with that of the human mRNAome and were also enriched for 3'-UTR introns and uORFs. Intriguingly, most mRNAs coding for NMD factors were among the NMD-sensitive transcripts, implying that the NMD process is autoregulated. These mRNAs all possess long 3' UTRs, and some of them harbor uORFs. Using reporter gene assays, we demonstrated that the long 3' UTRs of UPF1, SMG5, and SMG7 mRNAs are the main NMD-inducing features of these mRNAs, suggesting that long 3' UTRs might be a frequent trigger of NMD.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > Functional Genomics Center Zurich
Dewey Decimal Classification:570 Life sciences; biology
610 Medicine & health
Language:English
Date:2011
Deposited On:28 Feb 2012 13:44
Last Modified:05 Apr 2016 15:28
Publisher:Cold Spring Harbor Laboratory Press
ISSN:1355-8382
Free access at:PubMed ID. An embargo period may apply.
Publisher DOI:https://doi.org/10.1261/rna.030247.111
PubMed ID:22028362
Permanent URL: https://doi.org/10.5167/uzh-56858

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