Systemic DNA damage responses in aging and disease

Congenital defects in transcription-coupled nucleotide excision repair (TC-NER) lead to growth and mental retardation and premature ageing in Cockayne syndrome (CS) patients, while 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 DNA damage response (DDR) mechanisms in (postmitotic) 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/FoxO. We demonstrated that DAF-16 overcomes the growth arrest and enhances DNA damage resistance in somatic tissues even when the damage persists. We propose that IIS mediates DNA damage responses in somatic tissues and promotes maintenance of differentiated tissues through enhanced tolerance of DNA damage that accumulates with aging. Mechanistically, we determined that the conserved ERK1/2 MAPK pathway regulates the DAF-16-mediated DDR.

An integrated proteomics, phospoproteomics and lipidomics analysis of the in vivo response to persistent UV-induced DNA lesions revealed a comprehensive picture of the organism’s DDR. We determined a shift in proteostasis towards autophagy, a dampening of glucose and lipid metabolism, and functionally implicate IIS, EGF-, and AMPK-like signalling. We found striking similarities between the acute response to DNA damage and the proteome of aging animals thus further supporting the underlying role of DNA damage accumulation in the aging process. Our data provide new insights into the organism’s response program to DNA damage during development and aging and suggest new intervention targets for triggering stress responses to antagonize the detrimental consequences of genome instability.