期刊
NUCLEIC ACIDS RESEARCH
卷 46, 期 5, 页码 2417-2431出版社
OXFORD UNIV PRESS
DOI: 10.1093/nar/gkx1318
关键词
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资金
- Fondation ARC [PJA20151203415]
- ERA.Net RUS Plus [DNA PARYLATION] [306, RFBR-16-54-76010]
- Ministry of Education and Science of the Republic of Kazakhstan [0115RK02473, 0115RK03029]
- NU ORAU
- RSF [14-24-00038]
- French National Research Agency 'Labex program' [ARCANE project] [ANR-11-LABX-0003-01]
- Fondation ARC Postdoctoral Fellowship [PDF20110603195]
- CIENCIACTIVA/CONCYTEC Doctoral Fellowship
- National Laboratory Astana, Nazarbayev University, Astana, Republic of Kazakhstan
- Russian Science Foundation [17-24-00011] Funding Source: Russian Science Foundation
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 (similar to 3-kb) DNA molecules, PARP-mediated DNA PARy-lation 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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