The molecular defences against reactive oxygen species in yeast

Abstract

SummaryThere is rapidly expanding interest into the protective systems against reactive oxygen species (ROS) in the eukaryotic cell, now that the links between oxidative damage, various disease states, and ageing, are firmly established in higher organisms. Yeast molecular genetics should be able to provide powerful insight into these mechanisms; this potential is now starting to be exploited. A number of primary antioxidant activities and systems of metal-ion homeostasis or detoxification have now been demonstrated to contribute to oxidative-stress protection in yeast. Also, evidence is emerging that the oxidative-stress response of this organism is complex, involving separate transcription-factor responses to peroxide, superoxide anion and metal ions. Generation of reactive oxygen speciesYeasts, as aerobic cells, have to face the toxic side-effects of molecular oxygen, viz. the production of reactive oxygen species (ROS). ROS are generated during normal cellular metabolism (e.g., by the mitochondrial respiratory chain, and H 2 O 2 -generating reactions catalysed by oxidases). They can also originate from the presence of pro-oxidants, such as hydrogen peroxide, menadione or paraquat, in the medium; by increases in the oxygen pressure (hyperoxia or re-oxygenation of hypoxic cells); or by exposure to ionizing radiations. These ROS, notably superoxide (O 2 . 7) and hydroxyl (OH . ) radicals, hydrogen peroxide (H 2 O 2 ) and singlet oxygen ( 1 O 2 ), damage cellular components by oxidizing lipids, proteins and nucleic acids (Halliwell and Gutteridge, 1989). Under normal physiological conditions, antioxidant defence mechanisms are almost certainly adequate to maintain ROS at basal, unharmful levels and to repair cellular damages. These defences operate at different levels. Primary defences operate to neutralize ROS, while secondary defences repair or remove the products of oxidation damage to DNA, proteins and lipids. When ROS levels exceed the antioxidant capacity of the cells, an oxidative stress results. This review discusses current understanding of the effects of pro-oxidants, the oxidative-stress response and the acquisition of increased resistance to ROS in yeast. Molecular damages induced by ROSOxidative damage to DNA and nucleoproteins produces base and sugar damage, single-strand breaks, abasic sites and DNA-protein cross-links. Although the superoxide radical and H 2 O 2 do not react directly with DNA, OH . is generated from them by the metal-catalysed Fenton/Haber-Weiss reaction. This induces DNA damage in yeast cells (Frankenberg et al., 1993). One of the major products of base damage, 8-hydroxyguanine (8OHG), is detectable in yeast cells exposed to lethal concentrations of H 2 O 2 , but not the sublethal concentrations of H 2 O 2 that induce increased oxidative-stress resistance (Woodford et al., 1995). Furthermore, H 2 O 2 increases the frequency of intrachromosomal recombination in Saccharomyces cerevisiae, via the formation of hydroxyl radicals. It is therefore likely that oxidative DNA damage plays...

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