Abstract
We have observed low expression levels of MARVELD1, a novel tumor repressor, in multiple tumors; however, its function in normal cells has not been explored. We recently reported that MARVELD1 interacts with importin β1, which plays an important role in nonsense-mediated RNA decay(NMD). Here, we demonstrate that MARVELD1 substantially inhibits nonsense-mediated RNA decay by decreasing the pioneer round of translation but not steady-state translation, and we identify MARVELD1 as an important component of the molecular machinery containing UPF1 and Y14. Furthermore, we determined the specific regions of MARVELD1 and UPF1 responsible for their interaction. We also showed that MARVELD1 promotes the dissociation of SMG1 from UPF1, resulting in the repression of serine phosphorylation of UPF1, and subsequently blocks the recruitment of SMG5, which is required for ensuing SMG5-mediated exonucleolytic decay. Our observations provide molecular insight into the potential function of MARVELD1 in nonsense-mediated RNA decay.
Highlights
Nonsense-mediated mRNA decay (NMD) is a quality-control mechanism to eliminate premature termination codon (PTC)containing mRNAs that synthesize truncated proteins [1]
During the pioneer round of translation, newly synthesized mRNAs bound at the 5’ caps by the capbinding protein complex (CBC) CBP80-CBP20 are marked by exon junction complexes (EJCs) at exon–exon junctions [3]
The interaction and colocalization of MARVELD1 with CBP20 and importin β1 implied that MARVELD1 might play a role in the same biological processes in which CBP20 and/or importin β1 participate, such as nuclear transport of protein or RNA, cap processing of pre-RNA, pre-mRNA splicing, and nonsensemediated RNA decay (NMD) [1,11,12]
Summary
Nonsense-mediated mRNA decay (NMD) is a quality-control mechanism to eliminate premature termination codon (PTC)containing mRNAs that synthesize truncated proteins [1]. During the pioneer round of translation, newly synthesized mRNAs bound at the 5’ caps by the capbinding protein complex (CBC) CBP80-CBP20 are marked by exon junction complexes (EJCs) at exon–exon junctions [3]. Before this occurs, the transient and/or weak interaction between cap-bound CBP80 and UPF1, a key NMD factor, promotes NMD if the mRNA contains a premature termination codon (PTC) 50-55 nucleotides upstream of an EJC-bound exon–exon junction [4]. The interactions between the SMG5 complexes and UPF1 result in sequential remodeling of the mRNA surveillance complex for NMD induction and recycling of the ribosome, release factors and NMD factors [6]
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