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XPD/ERCC2 mutations interfere in cellular responses to oxidative stress

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Lerner, Leticia K. [1, 2] ; Moreno, Natalia C. [1] ; Rocha, Clarissa R. R. [1] ; Munford, Veridiana [1] ; Santos, Valquiria [1] ; Soltys, Daniela T. [1] ; Garcia, Camila C. M. [3] ; Sarasin, Alain [4] ; Menck, Carlos F. M. [1]
Número total de Autores: 9
Afiliação do(s) autor(es):
[1] Univ Sao Paulo, Inst Biomed Sci, Dept Microbiol, Ave Prof Lineu Prestes 1374, Ed Biomed 2, BR-05508900 Sao Paulo, SP - Brazil
[2] Med Res Council Lab Mol Biol, Cambridge CB2 0QH - England
[3] Univ Fed Ouro Preto, Dept Biol Sci, BR-35400000 Ouro Preto, MG - Brazil
[4] Univ Paris Sud, Inst Gustave Roussy, CNRS, UMR8200, F-94805 Villejuif - France
Número total de Afiliações: 4
Tipo de documento: Artigo Científico
Fonte: MUTAGENESIS; v. 34, n. 4, p. 341-354, JUL 2019.
Citações Web of Science: 0

Nucleotide excision repair (NER) is a conserved, flexible mechanism responsible for the removal of bulky, helix-distorting DNA lesions, like ultraviolet damage or cisplatin adducts, but its role in the repair of lesions generated by oxidative stress is still not clear. The helicase XPD/ERCC2, one of the two helicases of the transcription complex IIH, together with XPB, participates both in NER and in RNA pol II-driven transcription. In this work, we investigated the responses of distinct XPD-mutated cell lines to the oxidative stress generated by photoactivated methylene blue (MB) and KBrO3 treatments. The studied cells are derived from patients with XPD mutations but expressing different clinical phenotypes, including xeroderma pigmentosum (XP), XP and Cockayne syndrome (XP-D/CS) and trichothiodystrophy (TTD). We show by different approaches that all XPD-mutated cell lines tested were sensitive to oxidative stress, with those from TTD patients being the most sensitive. Host cell reactivation (HCR) assays showed that XP-D/CS and TTD cells have severely impaired repair capacity of oxidised lesions in plasmid DNA, and alkaline comet assays demonstrated the induction of significantly higher amounts of DNA strand breaks after treatment with photoactivated MB in these cells compared to wild-type cells. All XPD-mutated cells presented strong S/G2 arrest and persistent gamma-H2AX staining after photoactivated MB treatment. Taken together, these results indicate that XPD participates in the repair of lesions induced by the redox process, and that XPD mutations lead to differences in the response to oxidatively induced damage. (AU)

Processo FAPESP: 14/15982-6 - Consequências de deficiências de reparo de lesões no genoma
Beneficiário:Carlos Frederico Martins Menck
Linha de fomento: Auxílio à Pesquisa - Temático