RNA Homeostasis Governed by Cell Type-Specific and Branched Feedback Loops Acting on NMD

Huang, Lulu; Lou, Chih Hong; Chan, Wai-Kin; Shum, Eleen Y.; Shao, Ada; Stone, Erica L.; Karam, Rachid; Song, Hye Won; Wilkinson, Miles

doi:10.1016/j.molcel.2011.06.031

Cited by 200 publications

(307 citation statements)

References 67 publications

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“…1E). These results correlate with previous observations, referred to as feedback regulation 32 or autoregulation. 33 Finally, RNA-seq tags were piled up on the last exon of the RPL12 transcript variant 2, a known NMD target, 50 in response to UPF1 knockdown, indicating that the splicing variant recognized by NMD had escaped from degradation in response to UPF1 depletion (Fig.…”

Section: Resultssupporting

confidence: 93%

Identification of hundreds of novel UPF1 target transcripts by direct determination of whole transcriptome stability

et al. 2012

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Section: Resultssupporting

confidence: 93%

Identification of hundreds of novel UPF1 target transcripts by direct determination of whole transcriptome stability

et al. 2012

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“…Therefore the situation appears analogous to what occurs in higher eukaryotes in which such introns can trigger EJC-mediated NMD. NMD control of N. crassa upf1 mRNA stability might be exerted through recognition of its uORF stop codons as PTCs, as is the case for N. crassa arg-2 ( Figure 5A) and S. cerevisiae CPA1 (Gaba et al 2005), or through its relatively long 39-UTR ( Figure 1A) as is reported for metazoan UPF1 (Huang et al 2011;Longman et al 2013), but this remains to be determined.To our knowledge, this work represents the first demonstration of circuits that enables regulation at the level of mRNA stability for eRF1, eIF4a3, and Y14. Autoregulation of mRNA levels for NMD factors has been reported for metazoans (Huang et al 2011;Yepiskoposyan et al 2011; reviewed in Karam et al 2013;Longman et al 2013) and autoregulation of NMD and EJC factors has been reported for plants (Nyiko et al 2013).…”

mentioning

confidence: 81%

Control of mRNA Stability in Fungi by NMD, EJC and CBC Factors Through 3′UTR Introns

Zhang¹,

Sachs

2015

Genetics

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In higher eukaryotes the accelerated degradation of mRNAs harboring premature termination codons is controlled by nonsense-mediated mRNA decay (NMD), exon junction complex (EJC), and nuclear cap-binding complex (CBC) factors, but the mechanistic basis for this quality-control system and the specific roles of the individual factors remain unclear. Using Neurospora crassa as a model system, we analyzed the mechanisms by which NMD is induced by spliced 39-UTR introns or upstream open reading frames and observed that the former requires NMD, EJC, and CBC factors whereas the latter requires only the NMD factors. The transcripts for EJC components eIF4A3 and Y14, and translation termination factor eRF1, contain spliced 39-UTR introns and each was stabilized in NMD, EJC, and CBC mutants. Reporter mRNAs containing spliced 39-UTR introns, but not matched intronless controls, were stabilized in these mutants and were enriched in mRNPs immunopurified from wild-type cells with antibody directed against human Y14, demonstrating a direct role for spliced 39-UTR introns in triggering EJC-mediated NMD. These results demonstrate conclusively that NMD, EJC, and CBC factors have essential roles in controlling mRNA stability and that, based on differential requirements for these factors, there are branched mechanisms for NMD. They demonstrate for the first time autoregulatory control of expression at the level of mRNA stability through the EJC/CBC branch of NMD for EJC core components, eIF4A3 and Y14, and for eRF1, which recognizes termination codons. Finally, these results show that EJC-mediated NMD occurs in fungi and thus is an evolutionarily conserved quality-control mechanism.KEYWORDS nonsense-mediated mRNA decay (NMD); RNA stability; exon junction complex (EJC); cap-binding complex (CBC); spliced 39-UTR intron; post-transcriptional control; ribosome; translation; Neurospora crassa T HE nonsense-mediated mRNA decay (NMD) pathway targets mRNA for degradation through the recognition of translated termination codons determined to be premature (Nicholson et al. 2009;Kervestin and Jacobson 2012;Popp and Maquat 2013). The NMD pathway can degrade mRNAs that contain upstream open reading frames (uORFs) or long 39-UTRs. The termination-related processes that trigger uORFmediated or long 39-UTR-mediated NMD are considered to be similar (Amrani et al. 2004(Amrani et al. , 2006Nicholson et al. 2009) in that termination events occurring far from the context created by the mRNA poly(A) tail can result in mRNA degradation (the "faux-UTR" model). In higher eukaryotes, NMD can also act on mRNAs that contain an intron downstream of a termination codon, such as aberrantly spliced transcripts or 39-UTR introncontaining transcripts (Sauliere et al. 2010;Bicknell et al. 2012). When a spliced intron is positioned at least 50-55 nt downstream of a termination codon, the exon junction complex (EJC) positioned near the exon-exon junction is not displaced by translating ribosomes and its continued association with mRNA targets the mRNA for deg...

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“…3A). To test whether Rhox10 escapes MSCI, we assayed Rhox10 pre-mRNA level, as several studies have used pre-mRNA levels as a reliable measure of gene transcription rate (Imam et al 2009, Huang et al 2011. qRT-PCR analysis revealed that while Rhox10 pre-mRNA is extremely high in both undifferentiated type A spermatogonia and differentiating type A spermatogonia (type A 1-4 spermatogonia), its level drops sharply in all the more mature germ cell subsets, including pachytene spermatocytes, where MSCI occurs (Fig.…”

Section: Transcriptional Control Of Rhox10mentioning

confidence: 99%

Dynamic expression pattern and subcellular localization of the Rhox10 homeobox transcription factor during early germ cell development

Song¹,

Dann²,

McCarrey³

et al. 2012

Reproduction

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Homeobox genes encode transcription factors that regulate diverse developmental events. The largest known homeobox gene clusterthe X-linked mouse reproductive homeobox (Rhox) cluster -harbors genes whose expression patterns and functions are largely unknown. Here, we report that a member of this cluster, Rhox10, is expressed in male germ cells. Rhox10 is highly transcribed in spermatogonia in vivo and is upregulated in response to the differentiation-inducing agent retinoic acid in vitro. Using a specific RHOX10 antiserum that we generated, we found that RHOX10 protein is selectively expressed in fetal gonocytes, germline stem cells, spermatogonia, and early spermatocytes. RHOX10 protein undergoes a dramatic shift in subcellular localization as germ cells progress from mitotically arrested gonocytes to mitotic spermatogonia and from mitotic spermatogonia to early meiotic spermatocytes, consistent with RHOX10 performing different functions in these stages.

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RNA Homeostasis Governed by Cell Type-Specific and Branched Feedback Loops Acting on NMD

Cited by 200 publications

References 67 publications

Identification of hundreds of novel UPF1 target transcripts by direct determination of whole transcriptome stability

Identification of hundreds of novel UPF1 target transcripts by direct determination of whole transcriptome stability

Control of mRNA Stability in Fungi by NMD, EJC and CBC Factors Through 3′UTR Introns

Dynamic expression pattern and subcellular localization of the Rhox10 homeobox transcription factor during early germ cell development

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