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DNA damage responses in Aging- associated Diseases

Human DNA is constantly subjected to attacks by harmful environmental factors such as UV rays, tobacco smoke or toxic substances in food. Even normal metabolism can produce substances that damage the genome. Tens of thousands of DNA lesions occur daily in every cell, requiring highly efficient DNA repair machineries. Unrepaired DNA damage, however, can lead to functional decline of cells ultimately resulting in cell death and tissue degeneration. Given the importance of DNA damage as a casual factor for the aging process, scientists in Research Area C explore the underlying role of DNA damage in aging and cancer.

Despite highly complex DNA repair mechanisms constantly surveying the genome, DNA damage inevitably accumulates with increasing age. If the damage is too severe, cell death can occur, ultimately leading to loss of tissue integrity. Erroneous DNA repair, however, can lead to mutations, which in turn can give rise to tumorous cell growth. Consequently, the risk of developing cancer increases dramatically with age. Also, cancer cells may accrue additional mutations that giving rise to resistance against conventional radio- and chemotherapy.

Inborn defects in DNA repair genes can result in accelerated aging and increased cancer susceptibility. Premature aging – so called progeroid- syndromes are rare genetic disorders, in which DNA damage accumulates early in life due to DNA repair deficiencies, thus triggering aging-associated diseases already at a very young age.

Scientists in Research Area C are specifically seeking answers to the following questions:

  1. How do the highly complex DNA repair mechanisms function at a molecular level?
  2. How do cells and tissues respond to the accumulation of DNA damage and which reaction programs can support the maintenance of tissue functioning?
  3. Which genome maintenance factors play a role in counteracting the aging process and carcinogenesis?

Thus CECAD aims to further our understanding of aging-associated disorders – which will provide the necessary foundation for developing new strategies to extend healthspan and to prevent aging-associated diseases and tumour development.

Prof. Dr. H. Christian Reinhardt
Head of Research Area C – Principal Investigator, Department of Internal Medicine I
Tel.  +49 221 478 96701
christian.reinhardt[at]uk-koeln.de

Klinik I für Innere Medizin
Cologne Center for Genomics
Weyertal 115b
50931 Köln
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H. Christian Reinhardt

Prof. Dr. Björn Schumacher
Head of Research Area C – Principal Investigator, Chair for Genome Stability in Ageing and Disease
Tel.  +49 221 478 84202
bjoern.schumacher[at]uni-koeln.de

CECAD Cologne
CECAD Forschungszentrum
Joseph-Stelzmann-Str. 26

50931 Köln
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Björn Schumacher
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Figures
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Figure 1: Human endometrial carcinomas were stained with an antibody directed against p53. Accumulation of mutant p53 is represented by intense nuclear staining.

Figure 2-5: The longevity assurance factor DAF-16, a homolog of the human FOXO transcription factor, is activated in response to DNA damage in the nematode C. elegans (Fig. 2). Confocal imaging of DAF-16 tagged with the green fluorescence protein GFP and the GATA transcription factor EGL-27 tagged with the red fluorescence mCherry show nuclear localization of both DNA damage response factors in animals that were treated with UV (Fig. 3–5). EGL-27 mediates the DNA damage response of DAF-16 in antagonizing the detrimental consequences of genome instability during developmental growth and with aging.