Iron homeostasis and oxidative DNA damage

Abstract

The interplay between cellular iron homeostasis and metabolism of reactive oxidative species is reviewed, mainly from the viewpoint of the possible consequences for DNA damage inflicted by these species. It is shown that genetic manipulation of the iron homeostasis gene repertoire affects directly the response of DNA to the aggression by oxidant species. It is also shown that a condition of oxidative stress alters iron homeostasis, providing the perception that these two events are mutually dependent. The presence of iron in the nucleus is reviewed and new data are discussed ; pointing both to (i) the participation of iron as a ligand of an unknown chromatin component, and to (ii) mechanisms of active transport of iron into the nucleus. The question of which mechanism is more important for DNA strand breaks under oxidative stress, either a calcium-activated nuclease or OH radical generated by the Fenton reaction is discussed. New data are reviewed showing that the chemical nature of the 3'-terminus at the scission point confirms the OH radical attack mechanism. Finally, genetic manipulation experiments at the level of metallothionein and superoxide dismutase genes have allowed cells that have provided important information to engineered : (i) metallothionein seems to be a nuclear antioxidant protein, playing a protective role against attack to DNA and (ii) the Cu/Zn superoxide dismutase balance is a very crucial one ; an excess of this enzyme may down-regulate the synthesis of antioxidant proteins, rendering the cells more vulnerable to oxidative attack.