SMG-6 mRNA cleavage stalls ribosomes near premature stop codons in vivo

Author:

Kim John H1,Modena Matthew S1ORCID,Sehgal Enisha1,Courney Annie1,Neudorf Celine W2,Arribere Joshua A1ORCID

Affiliation:

1. Department of MCD Biology , UC Santa Cruz, California, USA

2. Department of Biomolecular Engineering , UC Santa Cruz, California, USA

Abstract

Abstract Nonsense-mediated mRNA decay (NMD) protects cells from the toxic and potentially dominant effects of truncated proteins. Targeting of mRNAs with early stop codons is mediated by the ribosome and spatiotemporally aligned with translation termination. Previously we identified a novel NMD intermediate: ribosomes stalled on cleaved stop codons, raising the possibility that NMD begins even prior to ribosome removal from the stop codon. Here we show that this intermediate is the result of mRNA cleavage by the endonuclease SMG-6. Our work supports a model in which ribosomes stall secondary to SMG-6 mRNA cleavage in Caenorhabditis elegans and humans, i.e. that the novel NMD intermediate occurs after a prior ribosome elicits NMD. Our genetic analysis of C. elegans’ SMG-6 supports a central role for SMG-6 in metazoan NMD, and provides a context for evaluating its function in other metazoans.

Funder

NIH

National Institute of General Medical Sciences

Publisher

Oxford University Press (OUP)

Subject

Genetics

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