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

Autor: Kajitani GS; Departamento de Microbiologia, Instituto de Ciências Biomédicas, Universidade de São Paulo, 05508-000 São Paulo, SP, Brazil; Núcleo de Pesquisa em Ciências Biológicas & Departamento de Ciências Biológicas, Instituto de Ciências Exatas e Biológicas, Universidade Federal de Ouro Preto, 35400-000 Ouro Preto, MG, Brazil., Nascimento LLS; Departamento de Microbiologia, Instituto de Ciências Biomédicas, Universidade de São Paulo, 05508-000 São Paulo, SP, Brazil; Department of Pediatrics/Rady Children's Hospital San Diego, School of Medicine, University of California, San Diego, CA 92093, USA., Neves MRC; Departamento de Microbiologia, Instituto de Ciências Biomédicas, Universidade de São Paulo, 05508-000 São Paulo, SP, Brazil., Leandro GDS; Departamento de Microbiologia, Instituto de Ciências Biomédicas, Universidade de São Paulo, 05508-000 São Paulo, SP, Brazil; Centro Andaluz de Biología Molecular y Medicina Regenerativa, Universidad de Sevilla-CSIC-Universidad Pablo de Olavide, Seville, Spain., Garcia CCM; Núcleo de Pesquisa em Ciências Biológicas & Departamento de Ciências Biológicas, Instituto de Ciências Exatas e Biológicas, Universidade Federal de Ouro Preto, 35400-000 Ouro Preto, MG, Brazil., Menck CFM; Departamento de Microbiologia, Instituto de Ciências Biomédicas, Universidade de São Paulo, 05508-000 São Paulo, SP, Brazil. Electronic address: cfmmenck@usp.br.
Jazyk: angličtina
Zdroj: Seminars in cell & developmental biology [Semin Cell Dev Biol] 2021 Jun; Vol. 114, pp. 20-35. Date of Electronic Publication: 2020 Nov 21.
DOI: 10.1016/j.semcdb.2020.10.009
Abstrakt: 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.
(Copyright © 2020 Elsevier Ltd. All rights reserved.)
Databáze: MEDLINE
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