Mechanisms of mRNA degradation

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  • Mechanisms of mRNA degradation
    • occurs in the cytoplasm in P-bodies and required ribonucleases for RNA degradation
    • several mechanisms
      • some mRNAs have a half-life which is influenced by their structure
        • their secondary conformations and the shapes they form via RNA-binding proteins making the mRNP
        • some mRNPs might be inherently more stably-packaged
        • degradation machinery could simply strip from and mRNA the proteins protecting it and then rely on random collisions with ribonucleases for it to be degraded - however this is not likely to be an efficient mechanism
      • Decapping, deadenylation and cleavage
        • the 5-cap, 5'UTR, 3'UTR and poly A tail can contribute to the stability of an mRNP particle
          • mRNAs can be degraded by attack at several of these regions
        • degredation of mRNA is directly linked to translation, as translationally-active mRNAs are protected from decay through their closed-loop conformation
          • whereby 5' cap interacts with the 3' polyA tail through eIF4G which keeps the 5' and 3' ends protected from exonuclease attack
        • 3 steps
          • 1) Decapping
            • 5' cap is removed from the mRNA by decapping proteins Dcp1 and Dcp2 which exist as a complex
              • the complex has preferences for sequences no longer than 25 nucleotides long, which protects mRNAs where the translation machinery has assembled from degradation as the translation factors mask the 5' end from the decapping complex
            • 2) 5' end of mRNA attacked by Xrn1 enzyme
              • progressive exonuclease that works in 5'-->3' direction
              • highly conserved in eukaryotes Drosophila orthologue = pacman protein
              • 2) Deadenylation - required to begin at 3' end
                • removal of polyA tail
                • By PARN (polyadenylated ribonuclease)
                • 3' end now susceptible to attack by 3'-->5' degradation
                  • carried out by protein complex exosome
                    • several subunits which form a ring around target DNA
                    • also contains RNA helicases which unwind higher-order structures aiding mRNA degradation
                • 3) mRNA degradation initiated by endonucleolytic cleavage
                  • not occur in all mRNAs, most often in RNA interference
                  • internal cleavage of the mRNA produced exposed 5' and 3' ends which can be attacked by Xrn1 and exosome respectively
    • AU-rich elements
      • found in 3'UTR
      • in up to 8% of human mRNAs
      • mediate mRNA decay through several trans-acting factors where phosphorylation of regulatory proteins affects their activity
      • several mRNAs that contain AU-rich elements encode oncogenes and cytokines
        • products are short-lived or required in quick bursts
          • therefore stability needs to be tightly controlled
      • specific sequences are varied but typically comprise AUUUA sequences
        • recognised by RNA binding proteins
          • AUF1
            • promotes mRNA decay following binding RNA recognition motifs near ARE sequences
          • tristetraprolin (TTP)
            • binds to a 3'UTR ARE sequence of the TNF-alpha gene
              • causes its destabilisation
          • HuR
            • stabilises mRNA when it binds mRNAs when it binds to AREs
              • unclear mechanism but thought they outcompete proteins that would otherwise destabilise the molecule (e.g. AUF1 or TTP)
    • other RNA elements affecting mRNA stability
      • even coding regions can promote decay
        • c-fos mRNA (where AREs were discovered)
          • has AU-rich elements in 3'UTR
            • also includes an AG-rich element in coding region that contributes to instability
        • such instability sequences contained in the ORF (coding region) are more likely to be present where the AA sequence of the protein encoded is less important
        • c-myc
          • contains instability elements within its ORF

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