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An update on the mechanisms and pathophysiological consequences of genomic instability with a focus on ionizing radiation

Authors Streffer C

Received 10 July 2015

Accepted for publication 8 September 2015

Published 1 December 2015 Volume 2015:6 Pages 225—233

DOI https://doi.org/10.2147/RRB.S72016

Checked for plagiarism Yes

Review by Single-blind

Peer reviewer comments 2

Editor who approved publication: Professor Zvi Kelman

Christian Streffer

Institute for Medical Radiobiology, University Clinics Essen, Essen, Germany

Abstract: The genome of eukaryotic cells is generally instable. DNA damage occurs by endogenous processes and exogenous toxic agents. The efficient DNA repair pathways conserve the genetic information to a large extent throughout the life. However, exposure to genotoxic agents can increase the genomic instability. This phenomenon develops in a delayed manner after approximately 20 and more cell generations. It is comparatively thoroughly investigated after the exposure to ionizing radiation. The increase of genomic instability has been observed after exposures to ionizing radiation in vitro and in vivo as well as with many different types of radiation. The effect is induced over a wide dose range, and it has been found with cell death, chromosomal damage, cell transformations, mutations, double-strand breaks, malformations, and cancers. No specific chromosomes or genomic sites have been observed for such events. The increased genomic instability can be transmitted to the next generation. Possible mechanisms such as oxidative stress (mitochondria may be involved), reduced DNA repair, changes in telomeres, epigenetic effects are discussed. A second wave of oxidative stress has been observed after radiation exposures with considerably high doses as well as with cytotoxic agents at time periods when an increased genomic instability was seen. However, the increase of genomic instability also happens to much lower radiation doses. Hypoxia induces an increase of genomic instability. This effect is apparently connected with a reduction of DNA repair. Changes of telomeres appear as the most probable mechanisms for the increase of genomic instability. Syndromes have been described with a genetic predisposition for high radiosensitivity. These individuals show an increase of cancer, a deficient DNA repair, a disturbed regulation of the cell cycle, and an increased genomic instability. Several studies with cancer patients show an increased genomic instability in the blood lymphocytes before any treatment has been performed. It is generally accepted that the increased genomic instability is a promotor for carcinogenesis.

Keywords: cancer, DNA repair, genomic instability, hypoxia, ionizing radiation

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