DNA PARYLATION: Study of the new post-replicational modification of DNA by Poly(ADP-ribose) polymerases and its implication for anticancer therapy
Acronyme: DNA PARYLATION
Call: RUS-PLUS JTC2015 “Joint call on Science and Technology”
Implementation period: 01.01.2016. – 31.07.2018.
Project coordinator: Institute of Chemical Biology and Fundamental Medicine SB RAS, Novosibirsk, Russia.
Centre National de la Recherche Scientifique, UMR 8200 “Stabilité génétique et oncogenèse”, Villejuif, France
Latvian Institute of Organic Synthesis, Riga, Latvia
Leader of Latvian team: Professor Nikolajs Sjakste
Total costs: 139 000 EUR
Costs for Latvian partner: 60 000 EUR
The aim of the present study is to obtain new insights into the molecular mechanisms of PARPs mediated regulation of DNA repair, DNA transcription, chromatin dynamics and cell death. Our preliminary studies suggest that the Poly(ADP-ribose) (PAR) polymerases, PARP1 and PARP2 can covalently modify not only acceptor proteins but also DNA termini at strand breaks by transferring ADP-ribose units to 3′-hydroxyl and/or 3¢-phosphate at the end of a gap and to 3¢-hydroxyl of a nucleotide at the end of a double-strand break.
Project proposes to develop new PARP and PARG inhibitors that can specifically inhibit DNA and/or proteins PARylation (dePARylation in case of PARG) and then examine their effects in vivo on cancer cell lines treated by DNA damaging agents.
The project is structured of four complementary tasks:
- Examination whether the PARylated termini of DNA strand breaks block DNA replication fork progression and inhibit the toxic non-homologous end-joining.
- Identification of PAR-DNA Adducts in living cells using biochemical and biophysical approaches.
- Biochemical characterization of substrate specificities of the members of PARP protein family.
- Development of new PARP and PARG inhibitors (directed by Latvian partner).
The major objectives of this task are to clarify the role of PARP and PARG proteins in DNA repair and to find new inhibition strategies. Recent results of Latvian team indicate that some derivatives of 1,4-dihydropyridines (1,4-DHPs), possessing anti-mutagenic activity can interact directly with DNA and, unexpectedly, with PARP1. This opens a possibility for search of novel inhibitors of PARP1 among 1,4-DHPs. Here, we propose to develop new PARP and PARG inhibitors that can specifically inhibit DNA and/or proteins PARylation (dePARylation in case of PARG) and then examine their effects in vivo on cancer cell lines treated by DNA damaging agents.