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

Gabriella Zarkovic, Ekaterina A. Belousova, Ibtissam Talhaoui, Christine Saint-Pierre, Mikhail M. Kutuzov, Bakhyt T. Matkarimov, Denis Biard, Didier Gasparutto, Olga I. Lavrik, Alexander A. Ishchenko

Результат исследования: Научные публикации в периодических изданияхстатьярецензирование

57 Цитирования (Scopus)


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.

Язык оригиналаанглийский
Страницы (с-по)2417-2431
Число страниц15
ЖурналNucleic Acids Research
Номер выпуска5
СостояниеОпубликовано - 16 мар. 2018


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