Journal
EMBO JOURNAL
Volume 41, Issue 10, Pages -Publisher
WILEY
DOI: 10.15252/embj.2021109202
Keywords
exon junction complex; mRNA degradation; nonsense mutations; nonsense-mediated mRNA decay; translation termination
Categories
Funding
- Pelotonia Graduate Fellowship program at OSU
- President's Postdoctoral Scholars program at OSU
- Pelotonia Postdoctoral Fellowship program at OSU
- Department of Physics Undergraduate Summer Research Scholarship at OSU
- Pelotonia Undergraduate Fellowship program at OSU
- College of Arts and Sciences Undergraduate Research Scholarship at OSU
- Center for RNA Biology Early-Stage Researcher Fellowship at OSU
- NIH [R01-GM120209, S10-OD023582]
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This study reveals that nonsense-mediated mRNA decay (NMD) in human cell lines can be dependent on UPF3B or independent of it. UPF3A only weakly activates NMD in wild-type cells, but strongly activates NMD in cells lacking UPF3B.
Nonsense-mediated mRNA decay (NMD) is governed by the three conserved factors-UPF1, UPF2, and UPF3. While all three are required for NMD in yeast, UPF3B is dispensable for NMD in mammals, and its paralog UPF3A is suggested to only weakly activate or even repress NMD due to its weaker binding to the exon junction complex (EJC). Here, we characterize the UPF3A/B-dependence of NMD in human cell lines deleted of one or both UPF3 paralogs. We show that in human colorectal cancer HCT116 cells, NMD can operate in a UPF3B-dependent and -independent manner. While UPF3A is almost dispensable for NMD in wild-type cells, it strongly activates NMD in cells lacking UPF3B. Notably, NMD remains partially active in cells lacking both UPF3 paralogs. Complementation studies in these cells show that EJC-binding domain of UPF3 paralogs is dispensable for NMD. Instead, the conserved mid domain of UPF3 paralogs is consequential for their NMD activity. Altogether, our results demonstrate that the mammalian UPF3 proteins play a more active role in NMD than simply bridging the EJC and the UPF complex.
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