ESR11: “NER-associated metabolic changes in age-related diseases”

UKK (B. Schumacher group): NER-associated metabolic changes in age-related diseases

i. Objective of research: To establish the metabolic alterations upon DNA damage-driven ageing.

ii. Current state of the art: We recently established the nematode for investigating the distinct outcomes of NER deficiencies in a simple metazoan model. Xeroderma pigmentosum (XP)-associated genetic defects lead to genome instability in proliferating cell types, while Cockayne syndrome (CS)-associated mutations impair developmental growth and tissue maintenance. Intriguingly, DNA damage in the proliferative compartment of C. elegans, the germline, evokes an innate immune response that triggers stress resistance throughout the animal. The “germline DNA damage induced systemic stress resistance” (GDISR) extends reproductive lifespan when germ cells require time to restore genome stability. Longevity assurance pathways also response to DNA damage in somatic tissues and enhance DNA damage tolerance thus enabling CS-like worms to pursue developmental growth and prolong tissue functioning with ageing despite persistent DNA damage. The C. elegans system is thus highly suitable for identifying physiological responses to DNA damage accumulation with ageing.

iii. Research methodology and approach: We will focus on investigating metabolic responses to persistent DNA damage in the context of disease-relevant DNA repair deficiencies. We will evoke persistent DNA damage by UV-treatment of NER deficient animals. We will then employ proteomics and lipidomics available in the UKK core facilities to explore the global metabolomics changes under the influence of persistent DNA damage. We will then utilize the C. elegans system to investigate genetically regulators of metabolic adjustments to genome instability. We will analyse tissue functionality and lifespan. We will furthermore use the synergies within aDDRess to extend our findings to the mammalian system. We will systemically assess parallels of metabolic responses to DNA damage with ageing in mammals. We will also target genes that we functionally identified in the metabolic regulation in C. elegans in the mammalian systems. Particularly, we will focus on mouse models of CS that are available in the aDDRess consortium.

iv. Originality and innovative aspects of the ESR project: Our proposed research will provide us with a systems level understanding onto the proteome and metabolic changes that occur upon exposure to DNA damage or with DNA damage-driven ageing in an intact organism.

v. Integration of the ESR project to the overall research programme: Our ESR will collaborate with the Garinis group on the MS-based protein identification of chromatin modulators in mammalian systems and with the Genevia on identifying relevant gene targets using next-generation sequencing approaches.