Transcription blockage by DNA damage in nucleotide excision repair-related neurological dysfunctions

Human genetic syndromes deficient in nucleotide excision repair (NER), such as xeroderma pigmentosum and Cockayne syndrome, may present neurological abnormalities and premature aging symptoms. Unrepaired endogenously generated DNA damage that hampers transcription is a strong candidate that contributes to the development of these severe effects in neuronal tissue. Endogenous lesions include those generated due to byproducts of cellular metabolisms, such as reactive oxygen species. This review presents much of the evidence on the mechanisms related to neurodegenerative processes associated with DNA damage responses. The primary focus is on the effects of the transcription machinery, including the accumulation of DNA•RNA hybrids (R-loops) that, in turn, influence DNA damage and repair metabolism. Moreover, several neuronal tissues present higher expression of long genes, a genomic subset more affected by DNA lesions, which may explain part of the neurological abnormalities in these patients. Also, neuronal tissues have different DNA repair capabilities that might result in different neurological consequences, as observed in patients and NER deficient animal models. The better understanding of how the accumulation of transcription blocking lesions can lead to neurological abnormalities and premature aging-like phenotypes may assist us in finding potential biomarkers and therapeutic targets that might improve the lives of these patients, as well as other neurological disorders in the general population.
This work was supported under the International Collaboration Research Funding from São Paulo Research Foundation (FAPESP, SP, Brazil) and the Netherlands Organization for Scientific Research – NWO (Grant #2019/19435-3). Financial support was also received from Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq, Grant #308868/2018-8) and Coordenação de Aperfeiçoamento de Pessoal do Ensino Superior (CAPES, Brasília, DF, Brazil, financial code 001).