SMD and NMD are competitive pathways that contribute to myogenesis: effects on PAX3 and myogenin mRNAs.
UPF1 functions in both Staufen 1 (STAU1)-mediated mRNA decay (SMD) and nonsense-mediated mRNA decay (NMD), which we show here are competitive pathways. STAU1- and UPF2-binding sites within UPF1 overlap so that STAU1 and UPF2 binding to UPF1 appear to be mutually exclusive. Furthermore, down-regulating the cellular abundance of STAU1, which inhibits SMD, increases the efficiency of NMD, whereas down-regulating the cellular abundance of UPF2, which inhibits NMD, increases the efficiency of SMD. Competition under physiological conditions is exemplified during the differentiation of C2C12 myoblasts to myotubes: The efficiency of SMD increases and the efficiency of NMD decreases, consistent with our finding that more STAU1 but less UPF2 bind UPF1 in myotubes compared with myoblasts. Moreover, an increase in the cellular level of UPF3X during myogenesis results in an increase in the efficiency of an alternative NMD pathway that, unlike classical NMD, is largely insensitive to UPF2 down-regulation. We discuss the remarkable balance between SMD and the two types of NMD in view of data indicating that PAX3 mRNA is an SMD target whose decay promotes myogenesis whereas myogenin mRNA is a classical NMD target encoding a protein required for myogenesis.
Gong
Chenguang
C
Department of Biochemistry and Biophysics, School of Medicine and Dentistry, University of Rochester, Rochester, New York 14642, USA.
Kim
Yoon Ki
YK
Woeller
Collynn F
CF
Tang
Yalan
Y
Maquat
Lynne E
LE
D000596:Amino Acids / Q000378:metabolism; D000818:Animals; D001665:Binding Sites; D019556:COS Cells; D002454:Cell Differentiation; D002460:Cell Line; D002522:Chlorocebus aethiops; D003598:Cytoskeletal Proteins / Q000378:metabolism; D015536:Down-Regulation; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D008870:Microtubules / Q000378:metabolism; D024510:Muscle Development / Q000502:physiology*; D032446:Myoblasts / Q000166:cytology / Q000378:metabolism; D018008:Myogenin / Q000378:metabolism*; D000072041:PAX3 Transcription Factor; D051761:Paired Box Transcription Factors / Q000378:metabolism*; D020871:RNA Stability / Q000502:physiology*; D012333:RNA, Messenger / Q000378:metabolism*; D016601:RNA-Binding Proteins / Q000378:metabolism; D015534:Trans-Activators / Q000378:metabolism
D000596:Amino Acids; D003598:Cytoskeletal Proteins; C503801:Myog protein, mouse; D018008:Myogenin; D000072041:PAX3 Transcription Factor; C489409:PAX3 protein, human; D051761:Paired Box Transcription Factors; D012333:RNA, Messenger; D016601:RNA-Binding Proteins; C492185:STAU1 protein, human; C492187:Stau1 protein, mouse; D015534:Trans-Activators; C068686:Pax3 protein, mouse