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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.

Author information

1
Department of Reproductive Medicine, School of Medicine, University of California San Diego, La Jolla, CA 92103, USA.
2
Department of Bioinformatics and Computational Biology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
3
Department of Biology, University of Texas at San Antonio, San Antonio, TX 78219, USA.
4
Department of Biology, Dartmouth College, Hanover, NH 03755, USA.
5
Reproductive Biology Group, Division of Developmental Biology, Department of Biology, Faculty of Science, Utrecht University, Padualaan 8, 3584 Utrecht, the Netherlands.
6
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: mfwilkinson@ucsd.edu.

Abstract

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.

PMID:
27040500
PMCID:
PMC4826573
DOI:
10.1016/j.cell.2016.02.046
[Indexed for MEDLINE]
Free PMC Article

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