Exploring the interaction between nucleotide excision repair pathways and Huntington disease: Implications for neurodegeneration and phenotypic overlap.

Under normal conditions DNA is constantly exposed to various endogenous and exogenous factors that induce DNA damage. To maintain and ensure its integrity, eukaryotic cells possess several complex DNA repair mechanisms. Each of these mechanisms is activated in response to DNA damage. Nucleotide excision repair (NER) is one of the most important and versatile DNA repair pathways, targeting the removal of bulky DNA lesions. Environmental agents (ultraviolet, component of solar radiation, ionizing radiation, chemotherapy) or cellular factors (oxidation, alkylation, hydrolysis and reactive oxygen species) can induce the activation of this system. NER dysfunction results in a heterogeneous group of autosomal recessive disorders (xeroderma pigmentosum (XP), Cockayne syndrome (CS), cerebro-oculo-facio-skeletal syndrome (COFS), trichothiodystrophy (TTD) and several overlapping syndromes, characterized by increased sensitivity to UV exposure, increased risk of tumor development, and importantly very frequently with neurodegeneration. In recent years, a Huntington's disease (HD)-phenotype has been described in NER disorders, broadening the differential diagnosis of patients who possess an HD-phenotype. Interestingly, several lines of evidence suggest a molecular overlap among adult neurodegenerative disorders, highlighting common mechanisms across neurodegeneration beyond DNA repair pathways. Moreover, at the intersection of NER disorders and HD, several converging pathogenic mechanisms have been reported, including impaired DNA repair, dysregulated transcriptional activity, defective proteostasis, oxidative stress, mitochondrial dysfunction, neuroinflammation, environmental contributors, and notably, compromised autophagy-particularly mitophagy. Herein, we explore the possible relation among NER repair defects, neurodegeneration, MMR dysfunction and HD. These findings may help to increase our understanding, opening new therapeutic avenues.