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Seminar

Tuesday, June 5th, 2018
10h30
Centre de Recherche - Paris - Amphith√©√Ętre Marie Curie

DNA Damage in G-Quadruplexes Regulates Gene Expression via Base Excision Repair

     Interplay between DNA repair of the oxidatively modified base 8-oxo-7,8-dihydroguanine (OG) and transcriptional activation has been observed in the VEGF, TNF-α, SIRT1, and BCL2 genes.  We synthesized OG into the VEGF potential G-quadruplex sequence (PQS) in the coding strand of a luciferase promoter to identify that base excision repair (BER) unmasked the G-quadruplex (G4) fold for gene activation.(1)  OG was site-specifically synthesized into a luciferase reporter plasmid to follow the time-dependent expression in mammalian cells when OG in the VEGF PQS context was located in the coding vs. template strand of the luciferase promoter.  Removal of OG from the coding strand by OG-glycosylase 1 (OGG1)-mediated BER upregulated transcription.  When OG was in the template strand in the VEGF PQS context, transcription was downregulated by a BER-independent process.(2)  By following the change in transcription up to 72 h, we could follow luciferase expression back to the background level that identified repair on the template strand was more efficient than on the coding strand of the promoter.  Reporters were also synthesized with an OG:A base pair that requires repair on both strands in order to return the sequence to a G:C base pair.  By monitoring the up/down luciferase expression, we followed the repair of an OG:A base pair occurring on both strands in mammalian cells.  Depending on the strand in which OG resides, this modification is an up/down regulator of transcription by coupling DNA repair with transcriptional activation.  The recent results further support a growing hypothesis that OG is an epigenetic-like DNA modification.(3-5)  Given that 50% of gene promoters in the DNA repair pathway may be controlled by G-quadruplexes, the concept emerges that these G-rich sequences act as sensors of oxidative stress providing redox-regulatory activity for gene expression. (6)

Event poster

Speaker(s)

Prof. Cynthia J. Burrows

Department of Chemistry, University of Utah, 315 S. 1400 East, Salt Lake City, UT 84112-0850, USA

Hosted by

Marie-Paule Teulade Fichou
Domain 1 - UMR 9187 / U1196 - Chemistry, Modelling and Imaging for Biology

Institut Curie

Contact

Marie-Paule Teulade Fichou

Institut Curie

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