mRNA Degradation Mechanisms

mRNA Decay and Degradation Processes

• A critical poly-A tail length leads to 3’-to-5’ degradation, possibly initiated by loss of poly-A binding proteins.
• Removal of the 5’ methyl cap can also cause rapid mRNA degradation.
• P bodies are cytoplasmic structures where RNA decay occurs, concentrating enzymes for 5’ to 3’ degradation pathways.
• Degradation and translation initiation compete; efficiency in one usually inversely affects the other.

Regulation of mRNA Stability

• AU-rich elements (AREs) in the 3’ UTR are recognized by proteins that increase deadenylation rates.
• Other RNA-binding proteins can stabilize mRNA when competing for binding, regulated by external signals (growth factors, hormones).

Structure of Mature mRNA

• Mature mRNA consists of three sections:
  • 5’ UTR with a methyl cap.
  • Open Reading Frame (ORF) framed by AUG start codon and stop codons (UAA, UAG, UGA).
  • 3’ UTR featuring a poly-A tail.
• For a gene encoding a 50 amino acid protein:
  • 5’ UTR = 50 nucleotides,
  • ORF = 150 nucleotides (50 amino acids).
  • 3’ UTR = 250 nucleotides.
  • Total mature mRNA length = 450 nucleotides.

mRNA Export Requirements

• Only properly processed mRNAs with correct capping, splicing, and poly-A tail are exported to the cytosol.
• Proteins involved in successful mRNA modifications:
  • Cap-binding protein (CBC).
  • Poly A binding protein (PABP).
  • Exon-junction complex (EJC).
• Eukaryotic initiation factors (eIFs) recognize bound proteins at 5’ and 3’ ends during translation initiation.

Translation-Dependent Surveillance Mechanisms

• Cells possess mechanisms for error detection in mRNA to prevent toxic protein products.
• Nonsense-mediated decay (NMD) specifically targets transcripts with premature termination codons (PTCs).

Control of mRNA Stability

• Longer mRNA half-lives correlate with greater protein translation capacity.
• "Housekeeping" genes often exhibit long half-lives due to constant need for basic cellular functions.
• Many mRNAs have shorter half-lives, particularly those coding for quickly variable proteins (growth factors, regulatory proteins).
• mRNA degradation rates can be regulated based on 3’ UTR sequences, affecting half-lives under different conditions.

mRNA Stability and Decay Mechanisms

• Gene expression can be influenced by mRNA half-life regulation, with decay rates being a significant factor.
• The length of the poly-A tail directly affects mRNA half-life; longer tails generally yield longer half-lives.
• AU-rich sequences in the 3’ UTR trigger poly-A tail removal.
• Specific regulators modulate mRNA half-life, as seen with transferrin receptor mRNA protection during iron scarcity.
• Dominant mRNA degradation pathway starts with gradual deadenylation, leading to either decapping and 5′→3′ decay or 3′→5′ decay.