AREs : decapping : DNA damage/repair : eIF4F : P-bodies : protein degradation : RNA decay :
Damaged DNA is repaired by a variety of mechanisms depending upon the nature of the damage. In eukaryotes , DNA damage elicits a multifaceted response that includes cell cycle arrest, transcriptional activation of DNA repair genes, and, in multicellular organisms, apoptosis. All organisms, prokaryotic and eukaryotic, utilize at least three enzymatic excision-repair mechanisms: base excision repair, mismatch repair, and nucleotide excision repair.
Rates of decay and translation of individual mRNAs in eukaryotic cells can be quite different, and both processes, which are coupled, can be regulated by during differentiation of by a variety of signals, including hormones and viral infection.
There are two major pathways of mRNA decay in eukaryotic cells – nonsense-mediated decay and nonstop decay. Both pathways begin with shortening of the 3' polyadenylate tail of eukaryotic mRNAs (deadenylation), which triggers:
a) decapping, leading to 5' to 3' exonucleolysis, or
b) exposure of the mRNA to 3' to 5' degradation.
The critical mRNA decay factors have been conserved in evolution and play a major role in the turnover of mRNAs in mammalian cells. The rate of decapping may be specified by a competition between the decapping enzyme and the cytoplasmic cap-binding, or eIF4F, complex, which binds the cap structure, promoting translation. Decapping requires dissociation of the cap-binding complex from the mRNA, and in the simplest model, the cytoplasmic cap-binding complex directly competes with the decapping machinery for the mRNA substrate, thereby modulating the rate of mRNA decay.
Eukaryotic cells can sequester mRNAs that are not engaged in translation into discrete cytoplasmic foci, referred to as processing bodies (P-bodies), which contain the proteins that activate or catalyze decapping. P-bodies also function in mRNA storage and are important for global and mRNA-specific regulation of translation, including the manner by which microRNAs can repress target mRNAs. P-bodies appear to be important sites for the control of cytoplasmic mRNA function.
The degradation of short-lived mRNAs, including cytokine and proto-oncogene transcripts, is regulated by proteins that bind to the AU-rich elements (AREs) in the 3' untranslated region of the transient mRNAs.
Just as cells repair DNA, the cellular stress response maintains the proteome by managing damaged proteins. However, protein degradation is part of normal cellular maintenance, and extensive, irreparable damage to proteins may trigger apoptosis.
Most intracellular protein degradation is directed by ubiquitin-tagging, and takes place at the proteasome, a multi-subunit protease present in the cytoplasm and the nucleus of eukaryotic cells.
Determinants of the half-life of proteins:
1. 'N-degron', N-end rule according to N-terminal amino acid (Ser long-lived → Asp short-lived),
2. amino acid sequences such as the PEST sequence, rich in proline, glutamic acid, serine, and threonine (if not masked by covalent attachment of phosphate groups to the side chains of certain amino acids),
3. exposure of degradation-signals in a partially unfolded state, allowing the signals to interact with the ubiquitin machinery, causing the protein to become tagged by ubiquitin (Ub). This reaction appears to be hindered by chaperone activity.
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