Intercellular communication of DNA damage and oxidative status underpin bystander effects

Abstract

Purpose: A well-known phenomenon in the field of radiation biology is that cells exposed to ionizing radiation (IR) (targeted cells) can induce in non-irradiated (non-targeted), bystander cells effects reminiscent of DNA damage responses (DDR) normally expected, exclusively in targeted cells. These phenomena are collectively referred to as radiation-induced bystander effects (RIBE) and have different manifestations depending on the endpoint studied. Although it is now recognized that RIBE reflects to a considerable extent communication by the targeted cells to undamaged cells of their damaged status, the molecular underpinnings of this communication and its significance for the organism are only partly understood. In particular, it remains unknown why and how targeted cells induce DNA damage in non-targeted, bystander cells threatening their genomic stability and risking thus their transformation to cancer cells. Here, we outline observations hinting to possible sources of artifacts in experiments designed to detect RIBE and summarize a model according to which targeted cells modulate their redox status as part of their overall response to IR and use this modified redox status as a source to generate signals that are transmitted to non-irradiated cells of the organism.

Material and methods: A synthesis of published evidence is presented.

Results: Depending on type, RIBE signals may be transmitted through various forms of direct intercellular contact, through molecules acting locally in a paracrine fashion, or through molecules acting remotely in an endocrine fashion. We reason that DNA damage generated in bystander cells is unlikely to manifest the clustered character exhibited in directly exposed cells and postulate that RIBE will depend on complications generated when simpler forms of damage encounter the DNA replication fork.

Conclusions: We suggest that RIBE result from intercellular communication mechanisms designed to spread within tissues, or the organism, alarm signals of DNA damage inflicted in subsets of the constituent cells. This response likely evolved to protect organisms by appropriately modulating stress response, repair or apoptosis, and may in some instances also cause adverse effects, e.g. as collateral damage.

Keywords:

• Bystander effects
• ionizing radiation
• oxidative stress
• intercellular communication
• DNA damage response

Disclosure statement

The authors report no conflicts of interest.

Additional information

Funding

This work was supported by grants from the “Bundesministerium für Bildung und Forschung” [BMBF: 02NUK005C and 03NUK001B] and the “Bundesministerium für Wirtschaft und Technologie” [BMWi: ESA-AO-08-IBER, 50WB1229].

Notes on contributors

Emil Mladenov

Emil Mladenov, Ph.D. in Molecular Biology. Current position: Research Associate at the Institute of Medical Radiation Biology, University of Duisburg-Essen Medical School, Essen, Germany. Expert in the field of DNA repair and Radiation Biology.

Fanghua Li

Fanghua Li, Ph.D. in Biophysics. Current position: Postdoctoral Fellow at the Institute of Medical Radiation Biology, University of Duisburg-Essen Medical School, Essen, Germany. Expert in the field of Bystander effects and DNA double strand break repair.

Lihua Zhang

Lihua Zhang, Ph.D. Radiation Biology. Expert in Radiation Biology. Discovered Factor Z.

Holger Klammer

Holger Klammer, Ph.D. Biology. Current position: Officer, The Federal Office for Radiation Protection. Expert in Bystander Effects and Radiation Protection.

George Iliakis

George Iliakis, Ph. D. in Biophysics. Current position: Director of the Institute of Medical Radiation Biology, University of Duisburg-Essen Medical School, Essen, Germany. Expert in the field of Radiation Biology and DNA double strand break repair.