DNA Repair Deficient Chinese Hamster Ovary Cells Exhibiting Differential Sensitivity to Charged Particle Radiation under Aerobic and Hypoxic Conditions

Ian M Cartwright,Victoria A Salinas,Akira Fujimori,Shigeaki Sunada,Hirokazu Hirakawa,Jeremy S Haskins,Mitsuru Uesaka,Takamitsu A Kato,Cathy Su,David J Chen,Hao Yu

doi:10.3390/ijms19082228

Abstract

It has been well established that hypoxia significantly increases both cellular and tumor resistance to ionizing radiation. Hypoxia associated radiation resistance has been known for some time but there has been limited success in sensitizing cells to radiation under hypoxic conditions. These studies show that, when irradiated with low linear energy transfer (LET) gamma-rays, poly (ADP-ribose), polymerase (PARP), Fanconi Anemia (FANC), and mutant Chinese Hamster Ovary (CHO) cells respond similarly to the non-homologous end joining (NHEJ) and the homologous recombination (HR) repair mutant CHO cells. Comparable results were observed in cells exposed to 13 keV/μm carbon ions. However, when irradiated with higher LET spread out Bragg peak (SOBP) carbon ions, we observed a decrease in the oxygen enhancement ratio (OER) in all the DNA of repair mutant cell lines. Interestingly, PARP mutant cells were observed as having the largest decrease in OER. Finally, these studies show a significant increase in the relative biological effectiveness (RBE) of high LET SOBP carbon and iron ions in HR and PARP mutants. There was also an increase in the RBE of NHEJ mutants when irradiated to SOBP carbon and iron ions. However, this increase was lower than in other mutant cell lines. These findings indicate that high LET radiation produces unique types of DNA damage under hypoxic conditions and PARP and HR repair pathways play a role in repairing this damage.

Highlights

Radiation-induced DNA damage results in chromosome aberrations, mutation, transformation, and cell death [1]
This study aims to investigate the role of various DNA repair pathways in response to DNA damage produced by high linear energy transfer (LET) radiation under hypoxic condition
It was observed that gamma-rays and low LET 13 keV/μm carbon ions showed a similar loss of radiation sensitivity under hypoxic conditions (Figure 1)

Summary

Introduction

Radiation-induced DNA damage results in chromosome aberrations, mutation, transformation, and cell death [1]. Double strand breaks are the most lethal form of DNA damage and are primarily repaired by the non-homologous end joining (NHEJ) and homologous recombination (HR) repair pathways. These repair pathways are cell cycle dependent, with NHEJ functioning in G1/S/G2 and HR only functioning in S/G2. The loss of these repair pathways results in hypersensitivity to ionizing radiation and other DNA damaging agents [3,4]. It has been well established that micronuclei can be utilized as a marker of radiation damage and radiation sensitivity [6,7,8,9]

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