MECHANISM OF ACTION OF THE TRANSCRIPTION REPAIR COMPLEX

Lab De Genetique Moleculaire Des Eucaryo, Strasbourg

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Abstract

The long-term objective of the proposed training is to provide biochemical evidence for a better model for the human diseases Cockayne syndrome (CS) and combined CS with features of xeroderma pigmentosum (XP/CS). By indication of the clinical manifestations of these diseases, the processes of transcription and/or DNA repair are essential to proper development and neurological function (CS) as well as guarding against predisposition towards skin cancer (XP). Employing active site mutations of CSB and biochemical analysis should allow a determination of which protein consumes ATP and what modifications result from its consumption (e.g. phosphorylation of the C-terminal domain (CTD) of RNA polymerase II (pol II)). Additional investigations seek to characterize the point of assembly of the pol II-CSB complex employing G-less cassette templates and gel shift methods. A second aim will investigate the model of the Pol II-CSB-TFIIH as a functional helicase by probing such complexes with KMn04. Additional investigations seek to determine the defects present in the assembly or activity of the helicase complex among samples from patients suffering from CS and combined XP/CS. The goal is to provide a better understanding of these DNA damage repair disorders. These and other contributions will be essential to the formulation of a better models for the developmental and neurologic diseases characteristic of CS, in addition to the skin cancer predisposition of XP.