SMD and NMD are competitive pathways that contribute to myogenesis: effects on PAX3 and myogenin mRNAs

Abstract

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.[Keywords: Staufen1-mediated mRNA decay; nonsense-mediated mRNA decay; Staufen1; UPF proteins; premature termination codon; myogenesis] Supplemental material is available at http://www.genesdev.org.

Non-coding RNAs in muscle differentiation and musculoskeletal disease

“…In particular, downregulating one of the m1/2-sbsRNAs, which is known to trigger SMD of the E3 ubiquitin ligase mRNA (Traf6), promoted myogenesis, and downregulation of Traf6 mRNA itself was found to inhibit myogenesis (119). Consistent with these findings, SMD was previously shown to increase during the differentiation of mouse myoblasts so as to augment the rate of myogenesis by degrading the mRNA encoding PAX3, which maintains myoblasts in an undifferentiated state (120).…”

Identification of elements in human long 3′ UTRs that inhibit nonsense-mediated decay

“…In addition, evidence suggests that NMD participates in regulation of normal gene expression by targeting a subset of normally processed mRNAs (Mendell et al 2004;Wittmann et al 2006;Viegas et al 2007;Huang et al 2011;Yepiskoposyan et al 2011;Tani et al 2012;Hurt et al 2013). Consistent with this, NMD contributes to important biological processes such as neuronal differentiation, myogenesis, T lymphocyte maturation, and inhibition of viral replication (Weischenfeldt et al 2008;Gong et al 2009;Bruno et al 2011;Frischmeyer-Guerrerio et al 2011;Balistreri et al 2014;Lou et al 2014).…”

High-resolution profiling of NMD targets in yeast reveals translational fidelity as a basis for substrate selection

“…However, NMD also targets a significant fraction of apparently normal and physiologically functional wild-type mRNAs (Schweingruber et al 2013), indicating that it also serves as a fundamental posttranscriptional regulatory mechanism for eukaryotic gene expression. Consistent with these important roles, NMD function is linked to diverse cellular processes, including cell growth and proliferation (Weischenfeldt et al 2008;Avery et al 2011;Lou et al 2014), development and differentiation (Medghalchi et al 2001;Metzstein and Krasnow 2006;Gong et al 2009;Wittkopp et al 2009), innate immunity (Gloggnitzer et al 2014), antiviral or stress responses (Sakaki et al 2012;Balistreri et al 2014), and neuronal activity or behavior (Giorgi et al 2007;Colak et al 2013).…”