"DNA damage is a fact of life. Lesions hamper genome function, induce mutations causing cancer and trigger senescence or cell death contributing to aging. Therefore cells are equipped with a sophisticated defence machinery: DNA Damage Response (DDR) including different repair pathways. Nucleotide excision repair (NER) is versatile repair process, eliminating helix-distorting lesions, e.g. bulky adducts and sun-induced lesions. Very cytotoxic transcription-blocking lesions are removed by a dedicated sub-pathway, transcription-coupled (TC-)NER. The impact of NER is highlighted by 4 disorders: xeroderma pigmentosum (XP), Cockayne syndrome (CS), trichothiodystrophy and UV-sensitive syndrome (UVSS). XP patients are cancer-prone due to global-genome (GG-)NER defects, whereas CS patients, impaired in TC-NER, display progeroid features, which are thought to derive from endogenous oxidative DNA lesions hampering transcription. Consistent with this, CS cells are sensitive to oxidative agents, whereas TC-NER-deficient UVSS patients are not sensitive to oxidative agents and do not display aging features. This implies lesion-specific TC-NER, arguing for distinct operational TC-repair machineries. The relative importance of DDR pathways varies with the type of damage, cell type and stage of development determining onset of cancer and aging pathologies. The challenging ambition of this proposal is to gain in depth insight into the role of NER in protection against cancer and aging by an integral multi-disciplinary approach which includes new mouse models for novel TC-NER genes, live cell and tissue NER kinetic analyses, advanced proteomics and analysis of NER-related chromatin dynamics to dissect cross-talk with other pathways. The strength of this project is the comprehensive strategy, availability of unique tools (e.g. collection of bona fide NER mutant mice), operational top notch technical platforms for all proposed approaches and proven competence and expertise."