IRON HOMEOSTASIS AND OXIDATIVE DNA-DAMAGE

The interplay between cellular iron homeostasis and metabolism of reac tive oxidative species is reviewed, mainly from the viewpoint of the p ossible consequences for DNA damage inflicted by these species, It is shown that genetic manipulation of the iron homeostasis gene repertoir e affects directly the response of DNA to the aggression by oxidant sp ecies. It is also shown that a condition of oxidative stress alters ir on homeostasis, providing the perception that these two events are mut ually dependent. The presence of iron in the nucleus is reviewed and n ew 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 me chanism is more important for DNA strand breaks under oxidative stress , either a calcium-activated nuclease or OH radical generated by the F enton reaction is discussed, New data are reviewed showing that the ch emical nature of the 3'-terminus at the scission point confirms the OH radical attack mechanism, Finally, genetic manipulation experiments a t the level of metallothionein and superoxide dismutase genes have all owed 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 di smutase balance is a very crucial one; an excess of this enzyme may do wnregulate the synthesis of antioxidant proteins, rendering the cells more vulnerable to oxidative attack,