Corneal Epithelial Nuclear Ferritin and Its Transporter Ferritoid Afford Unique Protection to DNA from UV Light and Reactive Oxygen Species

  • Thomas F. Linsenmayer
  • Kelly E. Beazley
  • Cindy X. Cai
  • James P. Canner
  • John M. Fitch
  • James K. Kubilus
  • John M. Millholland
  • Maria Nurminskaya
  • Christopher Talbot
  • Naomi B. Zak
Chapter
Part of the Oxidative Stress in Applied Basic Research and Clinical Practice book series (OXISTRESS)

Abstract

Ultraviolet (UV) light constitutes a major environmental hazard for all exposed tissues of the body. UV light can damage a variety of macromolecules—including alterations to DNA that are potentially carcinogenic. Much of the UV-induced damage to DNA is thought to result from the generation of reactive oxygen species (ROS) and the subsequent conversion of lowly-energetic ROS (e.g., H2O2) to highly energetic hydroxyl radicals. This occurs through the iron-mediated Fenton reaction. In skin, UV-induced damage to DNA is thought to be a major factor in the increasing incidence of epidermal cancers. However, corneal epithelial (CE) cells seem to be refractory to such damage—as primary cancers of these cells are extraordinarily rare—even though this tissue is transparent and constantly exposed to UV light. This suggests that CE cells have evolved a defense mechanism(s) that prevents damage to their DNA produced by both UV irradiation and ROS (e.g. H2O2). Studies in our laboratory suggest that one such mechanism involves having the iron-sequestering molecule ferritin in a nuclear localization—rather than cytoplasmic location it typically has in other cell types.

Other studies show that the subunit of this nuclear ferritin is a “typical” H-chain that is transported into the nucleus by a CE-specific nuclear transporter—we have termed ferritoid for its similarities to a ferritin subunit. Ferritoid has two functional domains. One is similar to ferritin and most likely facilitates binding to ferritin subunit(s); the other has a consensus SV40-like nuclear localization signal that is responsible for nuclear transport. Other studies show that ferritoid not only effects nuclear transport, as within the nucleus it remains associated with ferritin—participating in the formation of unique heteropolymeric complex(es). These complexes have unique structural and functional properties. These include a size which is half that of a “typical” cytoplasmic ferritin, a low content of iron, and the ability to bind to DNA—all of which may contribute to the prevention of damage to DNA.

Also, from studies on developing corneas, we have determined a number of additional properties of ferritoid and its interaction with ferritin. These include that: (1) temporally the synthesis of ferritoid and ferritin proteins are closely regulated—several hours before ferritin, (2) that iron and thyroxine are involved in regulating the synthesis of both ferritin and ferritoid, (3) the nuclear transport activity of ferritoid requires an interaction with ferritin, and (4) the interaction between ferritoid and ferritin involves phosphorylation of ferritoid.

Keywords

Ferritin Cornea Reactive oxygen species Ultraviolet light Ferritoid 

Notes

Acknowledgement

This work was supported by NIH Grant R01EY013127 to TFL.

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Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  • Thomas F. Linsenmayer
    • 1
  • Kelly E. Beazley
    • 2
  • Cindy X. Cai
    • 2
  • James P. Canner
    • 2
  • John M. Fitch
    • 2
  • James K. Kubilus
    • 1
  • John M. Millholland
    • 2
  • Maria Nurminskaya
    • 2
  • Christopher Talbot
    • 1
  • Naomi B. Zak
    • 2
  1. 1.Department of Integrated Physiology and PathobiologyTufts University Medical SchoolBostonUSA
  2. 2.BostonUSA

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