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Updated: Mar 27, 2026
Visualizing and Quantifying Endonuclease-Based Site-Specific DNA Damage
Published on: August 21, 2021
Cellular Repair and Removal of Protein-Damage Modifications
Abigail K D Porter1, Christina M Woo1,2
1Department of Chemistry and Chemical Biology, Harvard University, Cambridge, Massachusetts, USA;
Abstract:
Protein aging, stress, or metabolism can lead to the accumulation of numerous nonenzymatic chemical alterations that can threaten protein stability and function, particularly in long-lived proteins. Eukaryotic cells recognize these protein-damage events through repair and removal pathways, whose loss can lead to adverse effects and contribute to age-related disease pathogenesis. Here, we review recent advances in understanding the formation, repair, and removal mechanisms of posttranslational modifications arising from protein damage, including dehydroamino acids, early-stage glycation, isoaspartate, C-terminal cyclic imides, and C-terminal amides. We emphasize the emerging role of E3 ubiquitin ligases in facilitating the degradation of proteins bearing these modifications, highlight the approaches used to make these discoveries, and discuss the potential functions of these modifications beyond protein damage. Mounting evidence that protein-damage events influence cellular signaling and metabolism suggests the existence of vast undiscovered regulatory networks, creating opportunities to uncover tissue-specific repair mechanisms and their roles in development, aging, and stress responses across diverse biological contexts.
Insights
Cellular repair pathways remove damaged proteins, preventing age-related diseases. E3 ubiquitin ligases are key to degrading proteins with chemical alterations, revealing new regulatory networks.
Area of Science:
- Biochemistry
- Molecular Biology
- Cellular Biology
Background:
- Protein damage from aging, stress, or metabolism causes nonenzymatic chemical alterations.
- These alterations threaten protein stability and function, especially in long-lived proteins.
- Loss of cellular repair and removal pathways contributes to age-related disease pathogenesis.
Purpose of the Study:
- Review recent advances in understanding protein damage.
- Focus on formation, repair, and removal mechanisms of specific posttranslational modifications.
- Highlight the role of E3 ubiquitin ligases in protein degradation and discuss broader implications.
Main Methods:
- Literature review of recent scientific advances.
- Analysis of mechanisms for protein damage formation, repair, and removal.
- Emphasis on E3 ubiquitin ligases and their role in degrading modified proteins.
Main Results:
- Detailed review of posttranslational modifications from protein damage (dehydroamino acids, glycation, isoaspartate, cyclic imides, amides).
- Emerging role of E3 ubiquitin ligases in degrading proteins with these modifications.
- Evidence suggests protein damage influences cellular signaling and metabolism.
Conclusions:
- Protein damage and its repair/removal are critical in aging and disease.
- E3 ubiquitin ligases play a significant role in managing damaged proteins.
- Undiscovered regulatory networks involving protein damage exist, offering insights into development, aging, and stress responses.
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