Elsevier

Pharmacology & Therapeutics

Volume 154, October 2015, Pages 36-56
Pharmacology & Therapeutics

The DNA damage response and immune signaling alliance: Is it good or bad? Nature decides when and where

https://doi.org/10.1016/j.pharmthera.2015.06.011Get rights and content

Abstract

The characteristic feature of healthy living organisms is the preservation of homeostasis. Compelling evidence highlight that the DNA damage response and repair (DDR/R) and immune response (ImmR) signaling networks work together favoring the harmonized function of (multi)cellular organisms. DNA and RNA viruses activate the DDR/R machinery in the host cells both directly and indirectly. Activation of DDR/R in turn favors the immunogenicity of the incipient cell. Hence, stimulation of DDR/R by exogenous or endogenous insults triggers innate and adaptive ImmR. The immunogenic properties of ionizing radiation, a prototypic DDR/R inducer, serve as suitable examples of how DDR/R stimulation alerts host immunity. Thus, critical cellular danger signals stimulate defense at the systemic level and vice versa. Disruption of DDR/R–ImmR cross talk compromises (multi)cellular integrity, leading to cell-cycle-related and immune defects. The emerging DDR/R–ImmR concept opens up a new avenue of therapeutic options, recalling the Hippocrates quote “everything in excess is opposed by nature.”

Section snippets

The DNA damage response/repair and immune signaling networks: Is their intertwining a teleological demand?

To perform its physiological function, the cell requires, above all, the integrity of all of the encoded information it harbors. Experiencing numerous genotoxic insults on a daily basis, it has developed a highly conserved and sophisticated DNA damage recognition and repair network to cope with the variety of DNA lesions that occur. The DNA damage response (Jackson & Bartek, 2009) is a hierarchically structured signaling pathway consisting of DNA damage sensors, mediators, transducers, and

Evidence supporting a bidirectional connection between DDR/R and ImmR

Over the past years, our perception into the immunological properties of DNA and RNA has changed significantly, with studies demonstrating that nucleic acids trigger a robust ImmR under certain circumstances. The vigorous cellular reactions occurring after foreign genetic material is detected within the cytoplasm or the nucleus of eukaryotic cells as well as the systemic immune reactions occurring after DNA damage herald a new era in the conceptualization of the defense mechanisms of

The ATM apical DDR/R kinase as a hub of the DDR/R–ImmR network

It is well known that the main function of ATM is to coordinate the DDR/R network (Jackson & Bartek, 2009). However, ATM also responds to a wider variety of stressogenic stimuli, bringing about cellular reactions that aim to preserve cellular homeostasis (Shiloh & Ziv, 2013). Within this context, ATM seems to modulate NF-κB activity in a multifaceted manner.

One of the best characterized ATM–NF-κB interactions occurs in the cytoplasm where ATM assembles with ΙΚΚγ (NEMO) dimers, activating IκB

Questions and perspectives from the DDR/R–ImmR link in human diseases

Until now, with the exception of immune disorders linked to NHEJ defects, the DDR/R pathways were mainly examined with respect to cell-cycle-related defects, such as cancers, whereas the deregulated ImmR network was mainly studied related to infectious diseases and autoimmune disorders. From the concepts provided in this study, a common role of these interlinked networks in disease pathogenesis and development can be envisioned. For example, the recently proposed oncogene-induced model for

Conflict of interest

The authors declare no conflict of interest.

Acknowledgments

We would like to thank Christos P. Zampetidis for helping prepare the manuscript. This research has been cofinanced by the European Union (European Social Fund – ESF) and Greek national funds through the Operational Program “Education and Lifelong Learning” of the National Strategic Reference Framework (NSRF), Research Funding Program: Heracleitus II, and through the Operational NSRF-THALES (Grant number 379435) Investing in knowledge society through the European Social Fund. A.G.G is supported

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