Loss of tRNA methyltransferase 9 and DNA damage response genes in yeast confers sensitivity to aminoglycosides.
Bhavana VeerabhadrappaSudharshan SjNagashree N RaoMadhu DyavaiahPublished in: FEBS letters (2023)
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.
Keyphrases
- dna repair
- dna damage response
- dna damage
- wild type
- saccharomyces cerevisiae
- circulating tumor
- cell free
- reactive oxygen species
- single molecule
- oxidative stress
- induced apoptosis
- genome wide
- pseudomonas aeruginosa
- nucleic acid
- genome wide identification
- copy number
- cancer therapy
- acinetobacter baumannii
- cell cycle arrest
- drug delivery
- signaling pathway
- dna methylation
- cell proliferation
- transcription factor
- cell wall