Functional Analysis of TTDA: From Human to Mouse: Big impact of a small protein

Abstract

The integrity of genomic DNA is continuously exposed to intracellularly produced genotoxins, and environmental chemicals and radiation that lead to a wide variety of DNA lesions. To counteract the deleterious effects of DNA damage, all living organisms have developed multiple DNA repair mechanisms, each with their own lesion specificity and characteristics. Nucleotide excision repair (NER) is responsible for recognition and repair of numerous structurally unrelated helix-distorting lesions, including UV-induced 6-4-photoproducts (6-4PPs) and cyclobutane pyrimidine dimers (CPDs). TFIIH is an important multi-subunit protein complex crucial not only for NER, but also essential for RNA polymerase II (RNAP2) driven transcription. In both processes, TFIIH unwinds the DNA to allow either initiation of transcription or strand excision in NER. Mutations in the TFIIH subunits XPB, XPD and TTDA are associated with a large variety of clinical features associated 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 molecular mechanism underlying the clinical features presented in TTD patients, with a focus on the analysis of cellular features associated with inherited mutations in the TTDA gene.