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

Overview

Journal Cell

Publisher Cell Press

Specialty Cell Biology

Date 2016 Apr 5

PMID 27040500

Citations 94

Authors

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

Affiliations

Soon will be listed here.

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.

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