title: The Antagonistic Gene Paralogs Upf3a and Upf3b Govern Nonsense-Mediated RNA Decay.
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.
authors.affiliation: Department of Reproductive Medicine, School of Medicine, University of California San Diego, La Jolla, CA 92103, USA.
authors.forename: Eleen Y
authors.initials: EY
authors.lastname: Shum
authors.affiliation: Department of Reproductive Medicine, School of Medicine, University of California San Diego, La Jolla, CA 92103, USA.
authors.forename: Samantha H
authors.initials: SH
authors.lastname: Jones
authors.affiliation: Department of Reproductive Medicine, School of Medicine, University of California San Diego, La Jolla, CA 92103, USA.
authors.forename: Ada
authors.initials: A
authors.lastname: Shao
authors.affiliation: Department of Reproductive Medicine, School of Medicine, University of California San Diego, La Jolla, CA 92103, USA.
authors.forename: Jennifer N
authors.initials: JN
authors.lastname: Chousal
authors.affiliation: Department of Reproductive Medicine, School of Medicine, University of California San Diego, La Jolla, CA 92103, USA.
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Krause
authors.affiliation: Department of Bioinformatics and Computational Biology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Wai-Kin
authors.initials: WK
authors.lastname: Chan
authors.affiliation: Department of Reproductive Medicine, School of Medicine, University of California San Diego, La Jolla, CA 92103, USA.
authors.forename: Chih-Hong
authors.initials: CH
authors.lastname: Lou
authors.affiliation: Department of Reproductive Medicine, School of Medicine, University of California San Diego, La Jolla, CA 92103, USA.
authors.forename: Josh L
authors.initials: JL
authors.lastname: Espinoza
authors.affiliation: Department of Reproductive Medicine, School of Medicine, University of California San Diego, La Jolla, CA 92103, USA.
authors.forename: Hye-Won
authors.initials: HW
authors.lastname: Song
authors.affiliation: Department of Reproductive Medicine, School of Medicine, University of California San Diego, La Jolla, CA 92103, USA.
authors.forename: Mimi H
authors.initials: MH
authors.lastname: Phan
authors.affiliation: Department of Reproductive Medicine, School of Medicine, University of California San Diego, La Jolla, CA 92103, USA.
authors.forename: Madhuvanthi
authors.initials: M
authors.lastname: Ramaiah
authors.affiliation: Department of Reproductive Medicine, School of Medicine, University of California San Diego, La Jolla, CA 92103, USA.
authors.forename: Lulu
authors.initials: L
authors.lastname: Huang
authors.affiliation: Department of Biology, University of Texas at San Antonio, San Antonio, TX 78219, USA.
authors.forename: John R
authors.initials: JR
authors.lastname: McCarrey
authors.affiliation: Department of Biology, Dartmouth College, Hanover, NH 03755, USA.
authors.forename: Kevin J
authors.initials: KJ
authors.lastname: Peterson
authors.affiliation: Reproductive Biology Group, Division of Developmental Biology, Department of Biology, Faculty of Science, Utrecht University, Padualaan 8, 3584 Utrecht, the Netherlands.
authors.forename: Dirk G
authors.initials: DG
authors.lastname: De Rooij
authors.affiliation: Department of Reproductive Medicine, School of Medicine, University of California San Diego, La Jolla, CA 92103, USA.
authors.forename: Heidi
authors.initials: H
authors.lastname: Cook-Andersen
authors.affiliation: 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.
authors.forename: Miles F
authors.initials: MF
authors.lastname: Wilkinson
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D047108:Embryonic Development; D019143:Evolution, Molecular; D005718:Gametogenesis; D020131:Genes, Duplicate; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D059365:Nonsense Mediated mRNA Decay; D016601:RNA-Binding Proteins / Q000378:metabolism*
chemical_list: D016601:RNA-Binding Proteins; C000610227:UPF 3A protein, mouse; C585775:UPF3B protein, mouse