CECAD Universität zu Köln
Cluster of Excellence: Cellular Stress Responses in Aging-Associated Diseases

Björn Schumacher, Ph.D.

DNA Damage and Aging

We are investigating the molecular mechanism of aging. Aging is strongly correlated with a host of human pathologies, most prominently cancer and neurodegenerative diseases such as Alzheimer's and Parkinson's, as well as general functional decline. It is, therefore, of outstanding interest to further our understanding of the mechanisms underlying human aging. DNA damage has been shown to play a central role both in cancer and, more recently, in premature aging. The causal role of DNA damage in cancer and aging is particularly apparent in human patients that have inborn deficiencies in nucleotide excision repair (NER). There are two distinct branches of initial damage recognition; global genome (GG) NER scans the entire genome for helix-distorting DNA lesions, whereas transcription-coupled repair (TCR) detects lesions in actively transcribed genes. Strikingly, GG-NER defects leads to skin cancer prone Xeroderma pigmentosum (XP) whereas defective TCR gives rise to premature aging (progeroid) syndromes Cockayne syndrome (CS) and trichothiodystrophy (TTD). To unravel the molecular mechanism through which DNA damage contributes to aging we are using the genetic model organism Caenorhabditis elegans as well as mammalian disease models.

Excision repair in cancer and aging. UV lesions and helix-distorting chemical adducts are recognized and repaired by a multi-protein nucleotide excision repair (NER) complex comprising two pathways: global genome (GG) NER and transcription-coupled excision repair (TCR). Patients who have a defective GG-NER pathway are highly susceptible to skin cancer, whereas defects in TCR lead to progeroid syndromes. Reproduced from Schumacher, Bioessays 2009