Abstract
DNA damage is constantly produced by both endogenous and exogenous factors; DNA lesions then trigger the so-called DNA damaged response (DDR). This is a highly synchronized pathway that involves recognition, signaling and repair of the damage. Failure to eliminate DNA lesions is associated with genome instability, a driving force in tumorigenesis. Proteins carry out the vast majority of cellular functions and thus proteome quality control (PQC) is critical for the maintenance of cellular functionality. PQC is assured by the proteostasis network (PN), which under conditions of proteome instability address the triage decision of protein fold, hold, or degrade. Key components of the PN are the protein synthesis modules, the molecular chaperones and the two main degradation machineries, namely the autophagy-lysosome and the ubiquitin-proteasome pathways; also, part of the PN are a number of stress-responsive cellular sensors including (among others) heat shock factor 1 (Hsf1) and the nuclear factor erythroid 2-related factor 2 (Nrf2). Nevertheless, the lifestyle- and/or ageing-associated gradual accumulation of stressors results in increasingly damaged and unstable proteome due to accumulation of misfolded proteins and/or protein aggregates. This outcome may then increase genomic instability due to reduced fidelity in processes like DNA replication or repair leading to various age-related diseases including cancer. Herein, we review the role of proteostatic machineries in nuclear genome integrity and stability, as well as on DDR responses.
Highlights
The genome is continuously exposed to genotoxic attacks, by both endogenous and exogenous factors, which directly or indirectly cause DNA lesions
Supervised protein degradation allows rapid, and irreversible, turn-off of a protein’s function; this process is of critical importance for cellular function since there is a plethora of genome curation and stability related proteins that need to be eliminated by the cell through specific processes at the right moment in order to maintain genome integrity and eventually cellular homeodynamics and survival
Recent findings suggest that increased levels of p62/SQSTM1 due to autophagy inhibition could be responsible for reduced DNA damage response (DDR); these effects on DNA repair are likely promoted by p62/SQSTM1 that is localized in the nucleus [215,216]
Summary
The genome is continuously exposed to genotoxic attacks, by both endogenous and exogenous factors, which directly or indirectly cause DNA lesions. These lesions can induce several DNA structural changes such as oxidations, depurinations, depyrimidations and single (SSBs) or double (DSBs) strand breaks [1]. Cells contain a number of highly coordinated and wired protein machineries that execute DNA replication and/or relaxation-condensation and they detect and repair the various types of DNA damage. The latter mechanisms are known as the DNA damage response (DDR) pathways and are highly specialized in the recognition of damaged DNA from physiological structural changes. We discuss how proteotoxic stress and disruption of PN modules functionality impacts on genome stability and integrity
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