Loss of tRNA methyltransferase 9 and DNA damage response genes in yeast confers sensitivity to aminoglycosides.
FEBS Lett
; 597(8): 1149-1163, 2023 04.
Article
em En
| MEDLINE
| ID: mdl-36708127
ABSTRACT
tRNA methyltransferase 9 (Trm9)-catalysed tRNA modifications have been shown to translationally enhance the DNA damage response (DDR). Here, we show that Saccharomyces cerevisiae trm9Δ, distinct DNA repair and spindle assembly checkpoint (SAC) mutants are differentially sensitive to the aminoglycosides tobramycin, gentamicin and amikacin, indicating DDR and SAC activation might rely on translation fidelity, under aminoglycoside stress. Further, we report that the DNA damage induced by aminoglycosides in the base excision repair mutants ogg1Δ and apn1Δ is mediated by reactive oxygen species, which induce the DNA adduct 8-hydroxy deoxyguanosine. Finally, the synergistic effect of tobramycin and the DNA-damaging agent bleomycin to sensitize trm9Δ and the DDR mutants mlh1Δ, rad51Δ, mre11Δ and sgs1Δ at significantly lower concentrations compared with wild-type suggests that cells with tRNA modification dysregulation and DNA repair gene defects can be selectively sensitized using a combination of translation inhibitors and DNA-damaging agents.
Palavras-chave
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Saccharomyces cerevisiae
/
Proteínas de Saccharomyces cerevisiae
Tipo de estudo:
Diagnostic_studies
Idioma:
En
Ano de publicação:
2023
Tipo de documento:
Article