Nonsense-mediated mRNA decay (NMD) is normally thought to promote the accelerate

Question

Nonsense-mediated mRNA decay (NMD) is normally thought to promote the accelerated turnover of mutant mRNAs carrying premature termination codons (PTCs). However, it was recently found that the half-lives of about 10% of normal human mRNAs are also regulated by NMD. How was this percentage determined experimentally? What features might these mRNAs have to make them subject to NMD regulation?

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Explanation / Answer

The features of mRNAs that make them subject to NMD regulation are:

a. Selenoprotein mRNAs in whcih specialized UGA selenocysteine codons intrinsically direct translation termination

b. mRNAs characterized by upstream open translational reading frames (ORFs), introns withing their 3' untranslated regions (UTRs)

c. Non-sense containing transposon or retroviral sequences within their coding regions

d. Alternatively spliced mRNAs (in humans, 1/3 of alternatively spliced mRNAs are through to be directing NMD)

NMD targets are recognized based on the following two factors: Post splicing exon junction complex (EJC) of proteins that is deposited 20-24 nucleotides upstream of exon-exon junctions. Intron position within pre-mRNA is an important determinant of NMD. Non-sense codons located above 50-55 nucleotides upstream of an exon-exon junction elicit NMD decay.

The following factors are present in an EJC:

REF/Aly – recruits the mRNA export factor TAP that interacts with UAP56 and Y14

Y14 which forms a stable heterodimer with the mRNA export factor Magoh, it also interacts with the NMD factor Upf3 or Upf3X

Magoh – interacts with TPF

SRm160 – which functions in splicing and enhances mRNA export

RNPS1 – which functions in splicing and mRNA export and may also recruit Upf3, UPF3X,

UAP56, a dead-box RNA helicase that interacts with REF/Al

Eukaryotic transcription initiation factor 4AIII, which is a RNA helicase that interacts withY14 and forms the EJC platform

PYM – which forms a trimeric complex with Y14 and Magoh

MNL51, which associates with and stimulates the RNA – helicae activity of eIF4AIII

Acinus, which forms a stable heterodimers with RNPSI

SAP18

The sequence of events that occur in an NMD is listed below:

CPD80 abd CPD 20 associated with the 5’ caps of newly synthesized transcripts prior to pre-mRNA splicing

UPF1 NMD factor associates with caps by binding directly to CBP80

Upf3 of Upf3xNMD factor associates with Exon junction complex (EJC) of newly spliced mRNAs in the nucleus and is exported with mRNA to the cytoplasm

In the cytoplasm, Upf3 or Upf3X recruits the Upf2 NMD factor

mRNA export – pioneer round of translation. This is enhanced by PABPC1 bound to mRNA, they enhance pioneer round of translation by binding to eIF4G, which in turn binds to CBP80

Translation termination – occurs with binding of a tetrameric complex SURF

SUF is composed of Upf1 kinase Smg1, Upf1, eRF1 and eRF3 translation termination factors

If translation terminates above 50-55 nucleotides upstream of an exon-exon junction, at a premature termination codon (PTC), then NMD will occur

Upf1 bound to the EJC triggers Upf1 phosphorylation, thus activating NMD’s mRNA degrading activiry

mRNA that is immune to NMD escapes NMD, undergoes remodeling.

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