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Correlation between Iron Homeostasis and Oxidative Stress: Consequences for the Production of Oxidative Modifications in DNA

Grant number: 95/09442-6
Support type:Research Projects - Thematic Grants
Duration: July 01, 1996 - February 28, 2001
Field of knowledge:Biological Sciences - Biochemistry - Metabolism and Bioenergetics
Principal Investigator:Rogerio Meneghini
Grantee:Rogerio Meneghini
Home Institution: Laboratório Nacional de Luz Síncrotron (LNLS). Centro Nacional de Pesquisa em Energia e Materiais (CNPEM). Ministério da Ciência, Tecnologia, Inovações e Comunicações (Brasil). Campinas , SP, Brazil

Abstract

Iron ions have been implicated in the formation of oxygen reactive species. These can attack several cellular structures as well as to play a physiological role in several cellular events. We have been investigating the production of oxidative lesions in DNA mediated by iron. We hypothesized that there should be a correlation between iron homeostase and oxidative stress. In fact, recently we verified that iron homeostasis alteration by genetic manipulation results in an increased susceptibility of DNA to the formation of oxidative lesions. We also found the reverse, namely, that oxidative stress modifies the cellular iron homeostasis. In the present project we will proceed on this line of investigation with the following objectives: (1) To understand the mechanism of iron regulatory protein (IRE, a cytosolic protein responsible for the regulation of cellular iron homeostasis) by oxidative stress, which we recently described. (2) We will produce genetic modifications in the cells that are amenable to in vitro transformation assays envisaging modification in iron homeostasis. We will attempt to generate cells that take up iron in excess and then we will analyze if these cells are more susceptible to transformation as compared to the parental cells. (3) We will also make efforts in analyzing the structure of complexes of iron and oligonucleotides by physical methods including x-ray crystallography. (4) We will investigate iron localization in chromatin by elemental analysis, via electron microscopy based on differential loss of energy. (5) We recently verified that iron is taken up by nuclei through a process which is ATP-dependent. We are presently investigating if this ATP-dependence is due to the existence of a novel iron transport ATPase. (6) We plan to generate cells with high levels of superoxide dismutase by gene transfection. The aim is to identify the influence of the cellular level of superoxide on the production of oxidative DNA lesions. (AU)