19
views
0
recommends
+1 Recommend
0 collections
    0
    shares
      • Record: found
      • Abstract: found
      • Article: found
      Is Open Access

      DNA Damage Response and Immune Defense: Links and Mechanisms

      review-article

      Read this article at

      Bookmark
          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Abstract

          DNA damage plays a causal role in numerous human pathologies including cancer, premature aging, and chronic inflammatory conditions. In response to genotoxic insults, the DNA damage response (DDR) orchestrates DNA damage checkpoint activation and facilitates the removal of DNA lesions. The DDR can also arouse the immune system by for example inducing the expression of antimicrobial peptides as well as ligands for receptors found on immune cells. The activation of immune signaling is triggered by different components of the DDR including DNA damage sensors, transducer kinases, and effectors. In this review, we describe recent advances on the understanding of the role of DDR in activating immune signaling. We highlight evidence gained into (i) which molecular and cellular pathways of DDR activate immune signaling, (ii) how DNA damage drives chronic inflammation, and (iii) how chronic inflammation causes DNA damage and pathology in humans.

          Related collections

          Most cited references74

          • Record: found
          • Abstract: found
          • Article: not found

          Persistent DNA damage signaling triggers senescence-associated inflammatory cytokine secretion

          Cellular senescence suppresses cancer by stably arresting the proliferation of damaged cells1. Paradoxically, senescent cells also secrete factors that alter tissue microenvironments2. The pathways regulating this secretion are unknown. We show that damaged human cells develop persistent chromatin lesions bearing hallmarks of DNA double-strand breaks (DSBs), which initiate increased secretion of inflammatory cytokines such as interleukin-6 (IL-6). Cytokine secretion occurred only after establishment of persistent DNA damage signaling, usually associated with senescence, not after transient DNA damage responses (DDR). Initiation and maintenance of this cytokine response required the DDR proteins ATM, NBS1 and CHK2, but not the cell cycle arrest enforcers p53 and pRb. ATM was also essential for IL-6 secretion during oncogene-induced senescence and by damaged cells that bypass senescence. Further, DDR activity and IL-6 were elevated in human cancers, and ATM-depletion suppressed the ability of senescent cells to stimulate IL-6-dependent cancer cell invasiveness. Thus, in addition to orchestrating cell cycle checkpoints and DNA repair, a novel and important role of the DDR is to allow damaged cells to communicate their compromised state to the surrounding tissue.
            Bookmark
            • Record: found
            • Abstract: found
            • Article: not found

            ATM and related protein kinases: safeguarding genome integrity.

            Maintenance of genome stability is essential for avoiding the passage to neoplasia. The DNA-damage response--a cornerstone of genome stability--occurs by a swift transduction of the DNA-damage signal to many cellular pathways. A prime example is the cellular response to DNA double-strand breaks, which activate the ATM protein kinase that, in turn, modulates numerous signalling pathways. ATM mutations lead to the cancer-predisposing genetic disorder ataxia-telangiectasia (A-T). Understanding ATM's mode of action provides new insights into the association between defective responses to DNA damage and cancer, and brings us closer to resolving the issue of cancer predisposition in some A-T carriers.
              Bookmark
              • Record: found
              • Abstract: found
              • Article: not found

              p38MAPK is a novel DNA damage response-independent regulator of the senescence-associated secretory phenotype.

              Cellular senescence suppresses cancer by forcing potentially oncogenic cells into a permanent cell cycle arrest. Senescent cells also secrete growth factors, proteases, and inflammatory cytokines, termed the senescence-associated secretory phenotype (SASP). Much is known about pathways that regulate the senescence growth arrest, but far less is known about pathways that regulate the SASP. We previously showed that DNA damage response (DDR) signalling is essential, but not sufficient, for the SASP, which is restrained by p53. Here, we delineate another crucial SASP regulatory pathway and its relationship to the DDR and p53. We show that diverse senescence-inducing stimuli activate the stress-inducible kinase p38MAPK in normal human fibroblasts. p38MAPK inhibition markedly reduced the secretion of most SASP factors, constitutive p38MAPK activation was sufficient to induce an SASP, and p53 restrained p38MAPK activation. Further, p38MAPK regulated the SASP independently of the canonical DDR. Mechanistically, p38MAPK induced the SASP largely by increasing NF-κB transcriptional activity. These findings assign p38MAPK a novel role in SASP regulation--one that is necessary, sufficient, and independent of previously described pathways.
                Bookmark

                Author and article information

                Contributors
                Journal
                Front Genet
                Front Genet
                Front. Genet.
                Frontiers in Genetics
                Frontiers Media S.A.
                1664-8021
                09 August 2016
                2016
                : 7
                : 147
                Affiliations
                [1] 1Institute for Genome Stability in Ageing and Disease, Medical Faculty, University of Cologne Cologne, Germany
                [2] 2Cologne Excellence Cluster for Cellular Stress Responses in Aging-Associated Diseases, Center for Molecular Medicine Cologne and Systems Biology of Ageing Cologne, University of Cologne Cologne, Germany
                Author notes

                Edited by: Alexandros G. Georgakilas, National Technical University of Athens, Greece

                Reviewed by: Bjoern Schwer, Harvard Medical School, USA; Vassilis G. Gorgoulis, University of Athens, Greece

                *Correspondence: Björn Schumacher, bjoern.schumacher@ 123456uni-koeln.de

                This article was submitted to Systems Biology, a section of the journal Frontiers in Genetics

                Article
                10.3389/fgene.2016.00147
                4977279
                27555866
                e9904410-d810-48e9-b204-c649db03de1d
                Copyright © 2016 Nakad and Schumacher.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 04 June 2016
                : 28 July 2016
                Page count
                Figures: 2, Tables: 0, Equations: 0, References: 118, Pages: 10, Words: 0
                Funding
                Funded by: European Research Council 10.13039/501100000781
                Award ID: ERC-StG 260383-GENSTAGE
                Funded by: Deutsche Forschungsgemeinschaft 10.13039/501100001659
                Award ID: SFB829, SFB670, KFO286
                Funded by: European Commission 10.13039/501100000780
                Award ID: FP7-PEOPLE-ITN CodeAge 316354, FP7-PEOPLE-ITN aDDRess 316390, FP7-PEOPLE-ITN MARRIAGE 316964, Flag-Era-JTC2015 GRAPHENE
                Funded by: Bundesministerium für Bildung und Forschung 10.13039/501100002347
                Award ID: FKZ0315893
                Categories
                Genetics
                Review

                Genetics
                dna damage,dna damage response (ddr),immune defense,chronic inflammation,tumourigenesis
                Genetics
                dna damage, dna damage response (ddr), immune defense, chronic inflammation, tumourigenesis

                Comments

                Comment on this article