Systemic DNA Damage Responses in Development and Aging
Björn Schumacher
Institute for Genome Stability in Aging and Disease, Medical Faculty, Cologne Excellence Cluster for
Cellular Stress Responses in Aging-Associated Diseases (CECAD) Research Centre and Centre for
Molecular Medicine (CMMC), University of Cologne, Joseph-Stelzmann-Str. 26, 50931 Cologne,
Germany. bjoern.schumacher@uni-koeln.de
The causal contribution of DNA damage in driving the aging process has become evident in a variety of
progeroid syndromes that are caused by defects in DNA repair systems. Congenital defects in genome
maintenance mechanisms cause complex disease phenotypes characterized by developmental growth
failure, cancer susceptibility, and premature aging. The distinct human disease outcomes of DNA repair
defects become particularly apparent in syndromes caused by mutations in nucleotide excision repair
(NER). While transcription-coupled (TC-) NER defects lead to growth and mental retardation and premature
ageing in Cockayne syndrome (CS) patients, global-genome (GG-) NER mutations lead to highly skin
cancer prone Xeroderma pigmentosum (XP). Intriguingly, the distinct outcomes of NER deficiencies are
conserved in the simple metazoan C. elegans. TC-NER deficiency renders worms highly susceptible to
DNA damage during developmental growth and with aging, while GG-NER defects give rise to genome
instability in proliferating germ cells.
We employed the nematode model to investigate distinct response mechanisms to genome instability in
somatic tissues and in the germline. DNA damage that persists in somatic tissues leads to activation of the
insulin-like growth factor signalling (IIS) effector DAF-16. The FoxO transcription factor DAF-16 is efficiently
activated in response to DNA damage during development while its DNA damage responsiveness declines
with aging. We demonstrated that DAF-16 alleviates growth arrest and enhances DNA damage resistance
in somatic tissues even in the absence of DNA repair. We propose that IIS mediates DNA damage
responses in somatic tissues and that DAF-16 activity enables developmental growth amid persistent DNA
lesions and promotes tissue maintenance through enhanced tolerance of DNA damage that accumulates
with aging.
DNA damage that persists in germ cells leads to enhanced stress resistance of somatic tissues. The
“Germline DNA damage-induced systemic stress resistance” (GDISR) is mediated by the innate immune
system that is triggered by genomically compromised germ cells and executed through elevated activity of
the ubiquitin proteasome system (UPS) in somatic tissues. We propose that GDISR elevates somatic
endurance to extend reproductive lifespan when germ cells require time to reinstate genome stability before
resuming offspring generation.
Our findings suggest that somatic tissues adapt to distinct constraints of genome instability in the germline
and the soma: Developmental growth of somatic tissues can be sustained despite genome instability by
DAF-16-mediated DNA damage tolerance, while adult tissues adapt to the requirements of genomically
compromised in germ cells through GDISR.