Présentation
Seminar Structural Biochemistry and Chemistry Department
Tuesday 22 january 2019 at 2.00 pm
Salle AUDITORIUM CENTRE F. JACOB – CFJ RdC 17c
Dr. Shana Sturla
ETH Zurich
DNA adduct molecular probes: From mechanisms of mutagenesis to adduct mapping and amplification
Carcinogenesis can be associated with an ordered progression of acquired mutations, in some cases with significant portions corresponding to point mutations in critical cell growth regulating genes. The biological generation of chemical alkylating agents or reactive oxidation species from endogenous metabolic processes and chemical exposures can alter the structures of DNA bases in genomic DNA. Using chemistry-based approaches, we have characterized the influence of DNA alkylation on polymerase-mediated synthesis of DNA, including the use of novel synthetic damage-directed nucleoside probes to understand chemical factors that influence the fidelity of DNA synthesis. Additionally, with the aim of amplifying damaged DNA for diagnostic purposes, we have demonstrated the efficient and specific incorporation of synthetic nucleotides opposite a DNA adduct but not template bases as a marker for specific positions of alkylation in DNA. Finally, we have demonstrated the use of alkynylated nucloetides for click-labeling of DNA at positions of damage, allowing us to map the frequency of modifications as a function of local sequence characteristics and broad genomic features. These results provide new insight into how base misincorporations lead to mutations, together with chemical tools for locating DNA damage within sequence contexts on entire genomes.
Contact : Marcel Hollenstein
Groupe à 5 ans Chimie bioorganique des acides nucléiques
Marcel.hollenstein@pasteur.fr