Selenium Toxicity toward Yeast as Assessed by Microarray Analysis and Deletion Mutant Library Screen: A Role for DNA Repair

Selenium (Se) is a trace element that is essential for
human health
as it takes part in many cellular processes. The cellular response
to this compound elicits very diverse processes including DNA damage
response and repair. Because an inorganic form of Se, sodium selenite
(SeL), has often been a part of numerous studies and because this
form of Se is used as a dietary supplement by the public, here, we
elucidated mechanisms of SeL-induced toxicity in yeast Saccharomyces
cerevisiae using a combination of systematic genetic and
transcriptome analysis. First, we screened the yeast haploid deletion
mutant library for growth in the presence of this Se compound. We
identified 39 highly SeL sensitive mutants. The corresponding deleted
genes encoded mostly proteins involved in DNA damage response and
repair, vacuole function, glutathione (GSH) metabolism, transcription,
and chromatin metabolism. DNA damage response and repair mutants were
examined in more detail: a synergistic interaction between postreplication
(PRR) and homologous recombination (HRR) repair pathways was revealed.
In addition, the effect of combined defects in HRR and GSH metabolism
was analyzed, and again, the synergistic interaction was found. Second,
microarray analysis was used to reveal expression profile changes
after SeL exposure. The gene process categories “amino acid
metabolism” and “generation of precursor metabolites
and energy” comprised the greatest number of induced and repressed
genes, respectively. We propose that SeL-induced toxicity markedly
results from DNA injury, thereby highlighting the importance of DNA
damage response and repair pathways in protecting cells against toxic
effects of this Se compound. In addition, we suggest that SeL toxicity
also originates from damage to cellular proteins, including those
acting in DNA damage response and repair.