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Cell. 2016 Apr 7;165(2):382-95. doi: 10.1016/j.cell.2016.02.046. Epub 2016 Mar 31.

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

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Department of Reproductive Medicine, School of Medicine, University of California San Diego, La Jolla, CA 92103, USA.
Department of Bioinformatics and Computational Biology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Department of Biology, University of Texas at San Antonio, San Antonio, TX 78219, USA.
Department of Biology, Dartmouth College, Hanover, NH 03755, USA.
Reproductive Biology Group, Division of Developmental Biology, Department of Biology, Faculty of Science, Utrecht University, Padualaan 8, 3584 Utrecht, the Netherlands.
Department of Reproductive Medicine, School of Medicine, University of California San Diego, La Jolla, CA 92103, USA; Institute of Genomic Medicine, University of California, San Diego, La Jolla, CA 92103, USA. Electronic address:


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.

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