Synergic effects of base excision repair and oxidized dNTPs pool | 48278

Journal of Neurology & Neurophysiology

ISSN - 2155-9562

Synergic effects of base excision repair and oxidized dNTPs pool on trinucleotide repeat instability

3rd International Conference and Exhibition on Neurology & Therapeutics

September 08-10, 2014 Hilton Philadelphia Airport, USA

Margherita Bignami

Accepted Abstracts: J Neurol Neurophysiol

Abstract :

Several neurodegenerative diseases are caused by trinucleotide repeat (TNR) expansion. Although the mechanism is not fully understood, studies in the mouse R6/1 model for Huntington?s disease (HD) indicate that TNR expansion might depend on the lack of coordination between DNA polymerase β (POLβ)-dependent repair synthesis and FEN1 cleavage during base excision repair (BER) of the oxidized DNA base 8-oxo-7,8-dihydroguanine (8-oxoG). Synthetic 100bp duplex oligonucleotides containing 20 CTG/CAG repeats, an 8-oxoG located in the TNR and purified enzymes and/or cell free extracts were used to investigate the molecular basis of TNR expansion during BER of 8-oxoG. Our results indicate that one or two oxidized bases, located in the same strand at 2- or 7- repeat distance, are processed by long-patch BER and result in expansion of the filament. When repair assays were performed using dNTPs supplemented with 8-oxodGTP, incorporation of oxidized triphosphates also modulated TNR expansion. During POLβ-dependent repair synthesis 8-oxodGTP was incorporated opposite either C or A and the newly formed 8-oxoG:C and 8-oxoG:A mismatches became substrates for the OGG1 and MUTYH glycosylases. This processing creates closely spaced strand breaks on opposite DNA strands that would allow expansion of the duplex. In addition evidence of an oxidative stress was obtained in brain areas of the R6/2 HD mouse model. Finally expression of the OGG1 and MUTYH DNA glycosylases, as well as of other BER enzymes in the striatum of wild-type and R6/2 mice indicate that all these factors might participate in TNR expansion in non-replicating cells.

Biography :

Margherita Bignami is Head of the Unit of Experimental Carcinogenesis at the Istituto Superiore di Sanita?. She has published more than 100 papers in reputed journals and has been serving as an editorial board member of DNA repair and Mutation Research.