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Regulation, mechanisms and proposed function of ferritin translocation to cell nuclei

¹ Department of Neuroscience and Anatomy, Pennsylvania State University College of Medicine, Milton S. Hershey Medical Center, Hershey, PA 17033, USA
² Department of Biochemistry and Molecular Biology, Pennsylvania State University College of Medicine, Milton S. Hershey Medical Center, Hershey, PA 17033, USA
³ Department of Pathology, Pennsylvania State University College of Medicine, Milton S. Hershey Medical Center, Hershey, PA 17033, USA

^* Authors for correspondence (e-mail: jrc3{at}psu.edu , mfried{at}psu.edu and kjm13{at}psu.edu )

Accepted 26 February 2002

Ferritin is traditionally considered a cytoplasmic iron-storage protein, but recent reports indicate that it is also found in cell nuclei. Nuclear ferritin has been proposed to be involved in both the protection of DNA and the exacerbation of iron-induced oxidative damage to DNA. We demonstrate that H-rich ferritin is present in the nucleus of human astrocytoma tumor cells. To study the mechanism and regulation of ferritin translocation to the nucleus, we developed a cell culture model using SW1088 human astrocytoma cells. Changes in cellular iron levels, cytokine treatments and hydrogen peroxide exposure affected the distribution of ferritin between the cytosol and the nucleus. Ferritin enters the nucleus via active transport through the nuclear pore and does not require NLS-bearing cytosolic factors for transport. Furthermore, H-rich ferritin is preferred over L-rich ferritin for uptake into the nucleus. Whole cell crosslinking studies revealed that ferritin is associated with DNA. Ferritin protected DNA from iron-induced oxidative damage in both in vitro and in cell culture models. These results strongly suggest a novel role for ferritin in nuclear protection. This work should lead to novel characterization of ferritin functions in the context of genomic stability and may have unparalleled biological significance in terms of the accessibility of metals to DNA. The knowledge generated as a result of these studies will also improve our understanding of iron-induced damage of nuclear constituents.

Key words: Iron, Oxidative damage, DNA protection, Nuclear translocation

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