摘要：

markdownabstract__Abstract__The integrity of genomic DNA is continuously exposed to intracellularly producedgenotoxins, and environmental chemicals and radiation that lead to a wide variety ofDNA lesions. To counteract the deleterious effects of DNA damage, all living organismshave developed multiple DNA repair mechanisms, each with their own lesion specificityand characteristics. Nucleotide excision repair (NER) is responsible for recognition andrepair of numerous structurally unrelated helix-distorting lesions, including UV-induced6-4-photoproducts (6-4PPs) and cyclobutane pyrimidine dimers (CPDs). TFIIH is animportant multi-subunit protein complex crucial not only for NER, but also essential forRNA polymerase II (RNAP2) driven transcription. In both processes, TFIIH unwinds theDNA to allow either initiation of transcription or strand excision in NER. Mutations in theTFIIH subunits XPB, XPD and TTDA are associated with a large variety of clinical featuresassociated with inherited NER-disorders: cancer-prone Xeroderma Pigmentosum (XP),severe neuro-developmental and premature ageing syndromes Trichothiodystrophy (TTD)and Cockayne Syndrome (CS) or XP combined with CS (XP/CS) or TTD (XP/TTD).The work presented in this thesis is aimed to better understand the molecularmechanism underlying the clinical features presented in TTD patients, with a focus onthe analysis of cellular features associated with inherited mutations in the TTDA gene.

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