title: RNA homeostasis governed by cell type-specific and branched feedback loops acting on NMD.
abstract: Nonsense-mediated mRNA decay (NMD) is a conserved RNA decay pathway that degrades aberrant mRNAs and directly regulates many normal mRNAs. This dual role for NMD raises the possibility that its magnitude is buffered to prevent the potentially catastrophic alterations in gene expression that would otherwise occur if NMD were perturbed by environmental or genetic insults. In support of this, here we report the existence of a negative feedback regulatory network that directly acts on seven NMD factors. Feedback regulation is conferred by different branches of the NMD pathway in a cell type-specific and developmentally regulated manner. We identify feedback-regulated NMD factors that are rate limiting for NMD and demonstrate that reversal of feedback regulation in response to NMD perturbation is crucial for maintaining NMD. Together, our results suggest the existence of an intricate feedback network that maintains both RNA surveillance and the homeostasis of normal gene expression in mammalian cells.
authors.affiliation: Department of Reproductive Medicine, School of Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Lulu
authors.initials: L
authors.lastname: Huang
authors.forename: Chih-Hong
authors.initials: CH
authors.lastname: Lou
authors.forename: Waikin
authors.initials: W
authors.lastname: Chan
authors.forename: Eleen Y
authors.initials: EY
authors.lastname: Shum
authors.forename: Ada
authors.initials: A
authors.lastname: Shao
authors.forename: Erica
authors.initials: E
authors.lastname: Stone
authors.forename: Rachid
authors.initials: R
authors.lastname: Karam
authors.forename: Hye-Won
authors.initials: HW
authors.lastname: Song
authors.forename: Miles F
authors.initials: MF
authors.lastname: Wilkinson
mesh_terms: D051700:Activating Transcription Factor 3 / Q000378:metabolism; D015153:Blotting, Western; D025461:Feedback, Physiological; D005786:Gene Expression Regulation; D006367:HeLa Cells; D006706:Homeostasis; D006801:Humans; D020365:RNA Helicases; D034622:RNA Interference; D020871:RNA Stability; D012333:RNA, Messenger / Q000378:metabolism*; D015534:Trans-Activators / Q000037:antagonists & inhibitors
chemical_list: C490449:ATF3 protein, human; D051700:Activating Transcription Factor 3; D012333:RNA, Messenger; D015534:Trans-Activators; D020365:RNA Helicases; C101828:UPF1 protein, human