Direkt zum Inhalt | Direkt zur Navigation

Benutzerspezifische Werkzeuge

Sektionen
Project 30
Sie sind hier: Startseite / Individual Projects / Project 30

Project 30

Björn Schumacher

Mechanisms of innate immune responses to DNA damage

Institute for Genome Stability in Ageing and Disease
Cluster of Excellence: Cellular Stress Responses in Ageing-associated Diseases (CECAD), University of Cologne

Brief description in German
Das nukleare Genom ist ständigen Beschädigungen ausgesetzt. Die DNA Schadensantwort hält die Zellteilung an, um die Reparatur zu ermöglichen oder treibt die beschädigte Zelle in den programmierten Zelltod, um die Transformation in eine Krebszelle zu verhindern.

Zusätzlich zu dieser zellautonomen DNA Schadensantwort, wird auch das Immunsystem aktiviert. Das Immunsystem kann einerseits die Beseitigung beschädigter Zellen unterstützen, aber auch zu gefährlichen Entzündungen führen.

In letzter Zeit haben sich weitere, bislang wenig verstandene innate Immunreaktionen auf DNA Schäden abgezeichnet. So haben wir im Tiermodell des Fadenwurms C. elegans gezeigt, dass DNA Schäden in Keimzellen die innate Immunabwehr aktivieren, welche dann im gesamten Tier Resistenz nicht nur gegenüber Infektion, sondern verschiedenartigen Arten von Stress etabliert.

In diesem Projekt wollen wir neue Erkenntnisse gewinnen, wie das innate Immunsystem durch DNA Schäden aktiviert wird. Daraus erhoffen wir uns ein besseres Verständnis der Auswirkungen von DNA Schäden auf die Immunabwehr und den alternden Organismus zu gewinnen.

Summary
The genome is constantly attacked by endogenous and exogenous genotoxic stress. DNA damage can contribute to cancer development and accelerates the ageing process as evidenced by a wide variety of congenital DNA repair deficiencies (Schumacher et al, 2008a).

Recently, bacterial infections have also been shown to result in nuclear DNA damage (Chumduri et al, 2013; Bergounioux et al, 2012). It was suggested that this genotoxic activity might result in carcinogenic consequences of bacterial infections (Toller et al, 2011). Conversely, DNA damage can trigger innate immune responses (Muruve et al, 2008; Karpac et al, 2011; Gasser et al, 2005; Jiang et al, 2009).

In humans, the most well characterized example for immune responses to DNA damage are the inflammatory responses and systemic immune suppression upon UV-exposure of the skin (Schwarz & Schwarz, 2011). Both, mechanisms and consequences of the complex interactions between local and systemic immune responses to genotoxic stress are yet poorly understood.

We propose to employ the simple metazoan model organism Caenorhabditis elegans to explore the mechanisms of cell-autonomous innate immune responses to DNA damage. C. elegans germ cells can activate conserved DNA damage checkpoints and we have previously identified novel regulatory mechanisms of the conserved p53-mediated DNA damage-induced apoptosis pathway in the nematode worm (Schumacher et al, 2001; 2005b; 2005a).

We recently uncovered a novel type of DNA damage response that is triggered by an ERK1/2 MAPK induced innate immune response in C. elegans germ cells and results in systemic stress resistance through activation of the ubiquitin-proteasome system (UPS) in somatic tissues (Ermolaeva et al, 2013).

We have proposed that the elevated somatic stress resistance allows animals to extend reproductive lifespan when germ cells require time for DNA repair before offspring generation can resume. We have thus established a simple metazoan system to explore the mechanisms of a cell-autonomously triggered DNA damage induced innate immune response that results in paracrine and systemic stress resistance.

Within the CRC670, we will investigate the molecular mechanisms that link the detection of DNA damage to the cell-autonomous induction of innate immune gene expression. Following characterization of these genes and mechanisms in the C. elegans system, we aim to translate the insight with our cooperation partners within the CRC into murine models of DNA damage-induced inflammation and immunity.


List of publications resulting from the project

Edifizi D, Schumacher B. Genome Instability in Development and Aging: Insights from Nucleotide Excision Repair in Humans, Mice, and Worms. Biomolecules 2015, 5, 1855-1869

Torgovnick A, Schumacher B. DNA repair mechanisms in cancer development and therapy.
Front Genet. 2015, 6:157

Frommolt P, Schumacher B. Wormpath: searching for molecular interaction networks in Caenorhabditis elegans. Source Code Biol Med. 2015, 10:5

Castells-Roca L, Mueller M, Schumacher B. Longevity through DNA damage tolerance.
Cell Cycle. 2015,14(4):467-8.

Ermolaeva MA, Dakhovnik A, Schumacher B. Quality control mechanisms in cellular and systemic DNA damage responses. Ageing Res Rev. 2015, Jan 2. pii: S1568-1637(14)00144-5.

Mueller M, Castells-Roca L, Babu V, Ermolaeva MA, Müller RU, Frommolt P, Williams AB, Greiss S, Schneider JI, Benzing T, Schermer B, Schumacher B. DAF-16/FOXO and EGL-27/GATA promote developmental growth in response to persistent somatic DNA damage. Nat Cell Biol. 2014 Dec; 16(12):1168-79

Babu V, Hofmann K, Schumacher B. A C. elegans homolog of the Cockayne syndrome complementation group A gene. DNA Repair. 2014 Dec;24:57-62.

Nkuipou-Kenfack E, Koeck T, Mischak H, Pich A, Schanstra JP, Zürbig P, Schumacher B. Proteome analysis in the assessment of ageing. Ageing Res Rev. 2014 Sep 22. pii: S1568-1637(14)00105-6.

Ermolaeva MA, Schumacher B. Insights from the worm: The C. elegans model for innate immunity. Semin Immunol. 2014 May 20. pii: S1044-5323(14)00051-7.

Behrens A, van Deursen J, Rudolph KL, Schumacher B. Impact of genomic damage and ageing on stem cell function. Nat Cell Biol. 2014 Feb 28;16(3):201-7.

Wolters S, Ermolaeva M, Bickel J, Fingerhut J, Khanikar J, Chan R, Schumacher B Loss of C. elegans BRCA1 promotes genome stability during replication in smc-5 mutants. Genetics. 2014 Apr;196(4):985-99.

Ermolaeva M and Schumacher B. Systemic DNA damage responses: Organismal adaptations to genome instability. Trends Genet. 2014 Mar;30(3):95-102.

Ermolaeva M, Schumacher B. The innate immune system as mediator of systemic DNA damage responses. Commun Integr Biol. 2013 Nov 13;6(6):e26926.

Ermolaeva MA, Segref A, Dakhovnik A, Ou HL, Schneider JI, Utermöhlen O, Hoppe T, Schumacher B. DNA damage in germ cells induces an innate immune response that triggers systemic stress resistance. Nature. 2013 Sep 19;501(7467):416-20.