Chemotherapy-induced neuronal DNA damage: an intriguing toolbox to elucidate DNA repair mechanisms in the brain

Abstract

The accumulation of DNA damage and subsequent decline in cellular functions are significant factors contributing to aging and-age associated neurodegeneration. Mutations in the genes involved in DNA repair pathways have been linked to premature aging and age-related neurodegeneration. Although DNA repair mechanisms are remarkably preserved across species, our current knowledge of neuronal-specific DNA repair pathways largely stems from investigations carried out on cellular and animal models, mainly focusing on cancer-related research. While DNA repair mechanisms are generally efficient in correcting damage caused by internal and external sources, the regulation of these mechanisms in post-mitotic neuronal cells, which are non-dividing, is not well understood. Studies utilizing autopsy brain samples have identified specific types of DNA damage and repair proteins in human neurons. However, these findings are inadequate to fully understand the regulatory aspects of neuronal-specific DNA repair pathways. This understanding is crucial for developing mechanism-based drugs that can prevent neuronal cell death, a characteristic feature of neurodegenerative diseases. As a result, further research is required to understand the intricate regulation of the DNA repair mechanisms involved in maintaining genome integrity in neurons. Several chemotherapeutic drugs cause DNA damage or impede cell division and cell death. Drugs that are primarily known to induce DNA damage in dividing cells can also damage neuronal DNA. In this context, we propose that it may be worthwhile to consider the DNA damage response induced by chemotherapy in cancer survivors as a tool to understand definite neuronal DNA repair mechanisms.

Keywords

DNA damage response / DNA repair / Neurodegenerative diseases / Alzheimer’s disease / Parkinson’s disease / Chemotherapy

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