Proteins are vital for cellular processes and organism health. Maintaining protein homeostasis-a balance between production, folding, and degradation-is crucial. Disruption of this homeostasis can lead to protein aggregation, associated with neurodegenerative disorders like Alzheimer's disease. Cells have a protein quality control system to maintain homeostasis, which can be disrupted by overload or reduced capacity.
This thesis of Suzanne Dekker investigates whether genomic instability, caused by defects in the DNA damage response (DDR) or external factors, disrupts protein homeostasis and its consequences at cellular and organism levels. It demonstrates that both defective DDR and DNA damage increase protein aggregation. Long-term effects of DNA damage lead to structural and functional changes, which can be mitigated by strengthening the protein quality system through chaperone overexpression.
In fruit flies, DNA damage causes degenerative characteristics and shortened lifespan, along with protein aggregation in the brain. Chaperone overexpression reduces protein aggregation and partially restores lifespan. The results show that genomic instability disrupts protein homeostasis, contributing to degenerative diseases and aging. Influencing protein homeostasis through chaperones may be a way to limit the consequences of DNA damage.
