Ubiquitin Modification by the E3 Ligase/ADP-Ribosyltransferase Dtx3L/Parp9.
ADP-ribosylation of proteins is emerging as an important regulatory mechanism. Depending on the family member, ADP-ribosyltransferases either conjugate a single ADP-ribose to a target or generate ADP-ribose chains. Here we characterize Parp9, a mono-ADP-ribosyltransferase reported to be enzymatically inactive. Parp9 undergoes heterodimerization with Dtx3L, a histone E3 ligase involved in ... DNA damage repair. We show that the Dtx3L/Parp9 heterodimer mediates NAD+-dependent mono-ADP-ribosylation of ubiquitin, exclusively in the context of ubiquitin processing by E1 and E2 enzymes. Dtx3L/Parp9 ADP-ribosylates the carboxyl group of Ub Gly76. Because Gly76 is normally used for Ub conjugation to substrates, ADP-ribosylation of the Ub carboxyl terminus precludes ubiquitylation. Parp9 ADP-ribosylation activity therefore restrains the E3 function of Dtx3L. Mutation of the NAD+binding site in Parp9 increases the DNA repair activity of the heterodimer. Moreover, poly(ADP-ribose) binding to the Parp9 macrodomains increases E3 activity. Dtx3L heterodimerization with Parp9 enables NAD+and poly(ADP-ribose) regulation of E3 activity.
Mesh Terms:
Adenosine Diphosphate Ribose, Cell Line, Tumor, DNA Repair, HEK293 Cells, Humans, Mutation, NAD, Neoplasm Proteins, Neoplasms, Poly(ADP-ribose) Polymerases, Protein Binding, Protein Interaction Domains and Motifs, RNA Interference, Time Factors, Transfection, Ubiquitin, Ubiquitin-Protein Ligases, Ubiquitination
Adenosine Diphosphate Ribose, Cell Line, Tumor, DNA Repair, HEK293 Cells, Humans, Mutation, NAD, Neoplasm Proteins, Neoplasms, Poly(ADP-ribose) Polymerases, Protein Binding, Protein Interaction Domains and Motifs, RNA Interference, Time Factors, Transfection, Ubiquitin, Ubiquitin-Protein Ligases, Ubiquitination
Mol. Cell
Date: May. 18, 2017
PubMed ID: 28525742
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