Small-Molecule Chemical Probe Rescues Cells from Mono-ADP-Ribosyltransferase ARTD10/PARP10-Induced Apoptosis and Sensitizes Cancer Cells to DNA Damage.
Members of the human diphtheria toxin-like ADP-ribosyltransferase (ARTD or PARP) family play important roles in regulating biological activities by mediating either a mono-ADP-ribosylation (MARylation) of a substrate or a poly-ADP-ribosylation (PARylation). ARTD10/PARP10 belongs to the MARylating ARTDs (mARTDs) subfamily, and plays important roles in biological processes that range from cellular signaling, DNA repair, and cell proliferation to immune response. Despite their biological and disease relevance, no selective inhibitors for mARTDs are available. Here we describe a small-molecule ARTD10 inhibitor, OUL35, a selective and potent inhibitor for this enzyme. We characterize its selectivity profile, model its binding, and demonstrate activity in HeLa cells where OUL35 rescued cells from ARTD10 induced cell death. Using OUL35 as a cell biology tool we show that ARTD10 inhibition sensitizes the cells to the hydroxyurea-induced genotoxic stress. Our study supports the proposed role of ARTD10 in DNA-damage repair and provides a tool compound for selective inhibition of ARTD10-mediated MARylation.
Faculty of Biochemistry and Molecular Medicine, Biocenter Oulu, University of Oulu, Oulu 90014, Finland.
Harikanth
H
Venkannagari
Institute of Biochemistry and Molecular Biology, RWTH Aachen University, 52074 Aachen, Germany.
Patricia
P
Verheugd
Faculty of Biochemistry and Molecular Medicine, Biocenter Oulu, University of Oulu, Oulu 90014, Finland.
Jarkko
J
Koivunen
Faculty of Biochemistry and Molecular Medicine, Biocenter Oulu, University of Oulu, Oulu 90014, Finland.
Teemu
T
Haikarainen
Faculty of Biochemistry and Molecular Medicine, Biocenter Oulu, University of Oulu, Oulu 90014, Finland.
Ezeogo
E
Obaji
Faculty of Biochemistry and Molecular Medicine, Biocenter Oulu, University of Oulu, Oulu 90014, Finland.
Yashwanth
Y
Ashok
Faculty of Biochemistry and Molecular Medicine, Biocenter Oulu, University of Oulu, Oulu 90014, Finland.
Mohit
M
Narwal
Faculty of Biochemistry and Molecular Medicine, Biocenter Oulu, University of Oulu, Oulu 90014, Finland.
Taina
T
Pihlajaniemi
Institute of Biochemistry and Molecular Biology, RWTH Aachen University, 52074 Aachen, Germany.
Bernhard
B
Lüscher
Faculty of Biochemistry and Molecular Medicine, Biocenter Oulu, University of Oulu, Oulu 90014, Finland. Electronic address: lari.lehtio@oulu.fi.
Lari
L
Lehtiö
D036002:ADP Ribose Transferases / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D017209:Apoptosis / Q000187:drug effects*; D004249:DNA Damage / Q000187:drug effects*; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D006367:HeLa Cells; D006801:Humans; D008958:Models, Molecular; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D054852:Small Molecule Libraries / Q000737:chemistry / Q000494:pharmacology*
D004791:Enzyme Inhibitors; D011518:Proto-Oncogene Proteins; D054852:Small Molecule Libraries; D036002:ADP Ribose Transferases; C499627:PARP10 protein, human; D011065:Poly(ADP-ribose) Polymerases
ADP-ribosylation; ARTD100; DNA repair; PARP10; chemical probe; inhibitor