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Depletion of KIN17, a human DNA replication protein, increases the radiosensitivity of RKO cells

E Despras1, L Miccoli, C Créminon

  • 1CEA, Commissariat à l'Energie Atomique, Laboratoire de Génétique de la Radiosensibilité, Département de Radiobiologie et de Radiopathologie, Direction des Sciences du Vivant, Fontenay-aux-Roses 92265, France.

Radiation Research
|May 20, 2003
PubMed

Insights

The KIN17 protein, involved in DNA replication, is overproduced in tumor cells and may play a role in cancer progression. Reduced KIN17 levels increase sensitivity to ionizing radiation, suggesting its role in DNA repair.

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Cell Biology

Background:

  • The human KIN17 protein is a chromatin-associated factor implicated in DNA replication.
  • Overproduction of KIN17 protein is observed in certain tumor cell lines, notably higher in non-small cell lung cancer (H1299) than melanoma (MeWo).
  • Elevated KIN17 protein levels correlate with increased RPA70 protein content.

Purpose of the Study:

  • To investigate the role of KIN17 protein in DNA replication, DNA repair, and cancer.
  • To explore the relationship between KIN17 protein levels and tumorigenic phenotypes.
  • To determine the impact of KIN17 on cellular response to DNA damage, particularly ionizing radiation.

Main Methods:

  • Comparative analysis of KIN17 protein levels across 16 cell lines.
  • Assessment of KIN17 and RPA70 protein co-induction after ionizing radiation exposure.
  • Observation of KIN17 localization after etoposide treatment (a topoisomerase II inhibitor).
  • Cell cycle analysis using flow cytometry after KIN17-positive cell transfection.
  • Evaluation of radiosensitivity in cells with reduced KIN17 transcript levels.

Main Results:

  • Highest KIN17 protein levels were found in H1299 lung cancer cells, lowest in MeWo melanoma cells.
  • Higher KIN17 levels correlated with elevated RPA70 protein.
  • Ionizing radiation induced co-expression of chromatin-bound KIN17 and RPA70.
  • Etoposide treatment caused KIN17 to form intranuclear foci, suggesting association with unrepaired DNA sites.
  • KIN17-positive cells showed cell cycle shifts towards higher DNA content, indicating chromatin conformation defects.
  • Reduced KIN17 transcript levels resulted in a sixfold increase in radiosensitivity at 2 Gy.

Conclusions:

  • KIN17 protein may be a crucial component of the DNA replication machinery.
  • KIN17 participates in the cellular response to unrepaired double-strand breaks (DSBs).
  • Impairment of the KIN17 pathway leads to heightened sensitivity to ionizing radiation, suggesting its potential as a biomarker or therapeutic target in cancer.

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