The Antagonistic Gene Paralogs Upf3a and Upf3b Govern Nonsense-Mediated RNA Decay

Eleen Y. Shum, Samantha H. Jones, Ada Shao, Jennifer N. Chousal, Matthew D. Krause, Wai Kin Chan, Chih Hong Lou, Josh L. Espinoza, Hye Won Song, Mimi H. Phan, Madhuvanthi Ramaiah, Lulu Huang, John R. McCarrey, Kevin J. Peterson, Dirk G. De Rooij, Heidi Cook-Andersen, Miles F. Wilkinson

Research output: Contribution to journalArticlepeer-review

90 Scopus citations


Gene duplication is a major evolutionary force driving adaptation and speciation, as it allows for the acquisition of new functions and can augment or diversify existing functions. Here, we report a gene duplication event that yielded another outcome - the generation of antagonistic functions. One product of this duplication event - UPF3B - is critical for the nonsense-mediated RNA decay (NMD) pathway, while its autosomal counterpart - UPF3A - encodes an enigmatic protein previously shown to have trace NMD activity. Using loss-of-function approaches in vitro and in vivo, we discovered that UPF3A acts primarily as a potent NMD inhibitor that stabilizes hundreds of transcripts. Evidence suggests that UPF3A acquired repressor activity through simple impairment of a critical domain, a rapid mechanism that may have been widely used in evolution. Mice conditionally lacking UPF3A exhibit "hyper" NMD and display defects in embryogenesis and gametogenesis. Our results support a model in which UPF3A serves as a molecular rheostat that directs developmental events.

Original languageEnglish (US)
Pages (from-to)382-395
Number of pages14
Issue number2
StatePublished - Apr 7 2016
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)


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