Publicación:
Characterization of DNA ADP-ribosyltransferase activities of PARP2 and PARP3: New insights into DNA ADP-ribosylation

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Fecha
2018
Autores
Belousova E.A.
Biard D.
Gasparutto D.
Ishchenko A.A.
Kutuzov M.M.
Lavrik O.I.
Matkarimov B.T.
Saint-Pierre C.
Talhaoui I.
Zarkovic G.
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Oxford University Press
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Abstracto
Poly(ADP-ribose) polymerases (PARPs) act as DNA break sensors and catalyze the synthesis of polymers of ADP-ribose (PAR) covalently attached to acceptor proteins at DNA damage sites. It has been demonstrated that both mammalian PARP1 and PARP2 PARylate double-strand break termini in DNA oligonucleotide duplexes in vitro. Here, we show that mammalian PARP2 and PARP3 can PARylate and mono(ADP-ribosyl)ate (MARylate), respectively, 5'- and 3'-terminal phosphate residues at double- and single-strand break termini of a DNA molecule containing multiple strand breaks. PARP3-catalyzed DNA MARylation can be considered a new type of reversible post-replicative DNA modification. According to DNA substrate specificity of PARP3 and PARP2, we propose a putative mechanistic model of PARP-catalyzed strand break-oriented ADP-ribosylation of DNA termini. Notably, PARP-mediated DNA ADP-ribosylation can be more effective than PARPs' auto-ADP-ribosylation depending on the DNA substrates and reaction conditions used. Finally, we show an effective PARP3- or PARP2-catalyzed ADP-ribosylation of high-molecular-weight (∼3-kb) DNA molecules, PARP-mediated DNA PARylation in cell-free extracts and a persisting signal of anti-PAR antibodies in a serially purified genomic DNA from bleomycin-treated poly(ADP-ribose) glycohydrolase-depleted HeLa cells. These results suggest that certain types of complex DNA breaks can be effectively ADP-ribosylated by PARPs in cellular response to DNA damage.
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Fondation ARC (http://www.arc-cancer.net) [PJA20151203415 to A.A.I.]; ERA.Net RUS Plus (www.eranet-rus.eu) [DNA PARYLATION #306 to A.A.I., RFBR-16–54-76010 to O.I.L.]; Ministry of Education and Science of the Republic of Kazakhstan [programs 0115RK02473 and 0115RK03029 to B.T.M.]; NU ORAU (http://www.nu.edu.kz) (to B.T.M.); RSF Grant [14–24-00038 to O.I.L.]; French National Research Agency ‘Labex program’ [ARCANE project ANR-11-LABX-0003–01 to C.S.-P., D.G.]; Fondation ARC Postdoctoral Fellowship (http://www.arc-cancer.net) [PDF20110603195 to I.T.]; CIENCIACTIVA/CONCYTEC Doctoral Fellowship (www.cienciactiva.gob.pe) (to G.Z.). Funding for open access charge: National Laboratory Astana, Nazarbayev University, Astana, Republic of Kazakhstan.
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unclassified drug
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