#8 mRNA Stability

[steady state mRNA]

determined by rates of synthesis and decay regulated by cis-acting elements

mRNA half life

~1/5 of half life of cell, determines how rapidly protein synthesis can be shut off after transcription stops

Global decay

process of all mRNA decaying, polyA tail decrreases over time, deadenylation + decappping then degredation from both ends (3' exosome, 5' XRN1)

PolyA tail

act as inhibitors of decapping, may allow mRNA to form circles to help stabilize mRNA and block decapping

PAB1

cytoplasmic polyA binding protein, associated with eIF4G (subunit of translation initiation), released over time as PolyA tail shortens

CCR4/NOT complex

exonuclease that degrades polyA tail once PolyA binding proteins are released

DCP1/2

degrades 5' cap of mRNA after mRNA cannot be circularized anymore

Processing (P) bodies

cytoplasmic liquid-liquid phase separated domains where mRNA decay factors are concentrated, sites of mRNA degradation or storage for translationally repressed mRNAs + degrading enzymes

Nonsense mediated decay

mRNA surveillance' eliminates mRNAs with premature termination codons within protein coding region to prevent synthesis of deleterious proteins, requires one round of translation initiation to function, important for embryonic development/SC differentiation,

Downstream marker model

last exon-exon junction defines a premature termination codon for NMD initiation, degradation by cleavage/decapping/deadenylation

Exon junction complex

splicing-dependent export factor, deposited by spliceosome ~20 nts upstream of exon-exon junction, influences export/translation/mRNA stability

SURF

surveillance complex, bind to release factors on terminating ribosome, phosphorylation of UPF1 is stimulated by downstream EJC (DECID)

UPF1

when phosphorylated, recruits decay factors to mRNA (SMG6)

SMG6

endonuclease that binds to phosphorylated UBF1

SMG5/7

adatper proteins bind UBF1, promote deadenylation/decapping

Intron-less PTCs

yeast have intronless mRNAs, contain a downstream element to define the PTC via interaction with Hrp1

Hrp1

RNA binding protein, cannot be displaced by ribosomes if in presence of a downstream element, signals to NMD machinery of PTC

Faux 3' UTR model

measure distance between termination codon and polyA tail (Pab1 binding) to check if it is abnormally long

Ribosome associated quality control (RQC)

mRNA decay pathways that are initiated when translating ribosomes stall/collide via collision sensors, RP ubiquitylation, mRNA cleavage/degradation, 80S ribosome splitting, nascent chain degradation

No go decay (NGD)

mRNA decay caused by stalling of TL in coding body of mRNA

Non-stop decay (NSD)

decay of mRNAs lacking a stop codon

Specific decay

mRNA decay that occurs because of specific decay signals (ex. sequence elements)

AREs

AU-rich element (AUUUA), in 3' UTRs of short-lived mRNAs, most destabilizing, bound by ARPs

ARE-binding protteins (ABPs)

control stability of ARE-mRNAs, can be positive or negative effect on mRNA stability,

AUF1

binding to ARE causes rapid and complete deadenylation by reducing affinity of PABP for the PolyA tail

HuR

binding to ARE causes stabilization by enhancing affinity of PABP for the PolyA tail

TTP

binding to ARE causes instability due to active recruitment of CCR4/Not complex (major deadenylase) and decapping complex

Trasferrin receptor (TfR)

mediates uptake of iron from blood, stability regulated by IRE

IRE

Iron response element within TfR mRNA, stem loop strucutre

IRE-BP

IRE binding protein, aconitase in presence of iron, when bound to 3' UTR prevents nucleolytic attack