DNA repair is a crucial process for organism to protect cells and tissues against from degeneration due to accumulation of DNA damage. One vital repair pathway is Nucleotide Excision repair (NER), which repairs (UV induced) helix distorting DNA lesions. When genes in this pathway are defective this can have severe consequences for the organism as illustrated by three human inherited disorders; Xeroderma pigmentosum (XP), Cockayne syndrome (CS) and Trichothiodystrophy (TTD).
XP patients have a high risk for skin cancer, but do not show any aging symptoms, whereas CS and TTD are characterized by growth retardation, cachexia and premature death. In CS, mutations are found in the CSA or CSB gene which is involved in a subpathway of NER, the transcription coupled repair pathway (TC-NER), which removes transcription blocking lesions. In TTD either the XPD, XPB or TTDA gene are mutated, which are part of the TFIIH complex. They are involved in unwinding the DNA around a lesion to make it accessible for the DNA repair machinery, but also play a role in transcription.
Within the department of Genetics several mouse models have been made with mutations in NER genes, which similar to the human syndromes show a plethora of aging symptoms. The CSB mouse, as the CS patient, has a progeroid phenotype, including retarded growth, mild neurological abnormalities and they become both blind and deaf with age.
Similarly, the TTD mouse represents a very good model for the corresponding human disease. When both mouse models are crossed to an XPA mouse, which is defective in the entire NER pathway, the aging phenotype is exacerbated. We will construct with this project a novel white-adipose tissue tissue specific aging mouse model that we will characterize in detail with the various targeted metabolomics platforms designed in the QP projects.