2. Academic Validation
  3. Ubiquitin Modification by the E3 Ligase/ADP-Ribosyltransferase Dtx3L/Parp9

Ubiquitin Modification by the E3 Ligase/ADP-Ribosyltransferase Dtx3L/Parp9

  • Mol Cell. 2017 May 18;66(4):503-516.e5. doi: 10.1016/j.molcel.2017.04.028.
Chun-Song Yang 1,  Kasey Jividen 1,  Adam Spencer 1,  Natalia Dworak 1,  Li Ni 1,  Luke T Oostdyk 2,  Mandovi Chatterjee 1,  Beata Kuśmider 1,  Brian Reon 3,  Mahmut Parlak 4,  Vera Gorbunova 5,  Tarek Abbas 6,  Erin Jeffery 7,  Nicholas E Sherman 7,  Bryce M Paschal 8
Affiliations

Affiliations

  • 1 Center for Cell Signaling, University of Virginia, West Complex, 1335 Lee Street, Charlottesville, VA 22908, USA.
  • 2 Center for Cell Signaling, University of Virginia, West Complex, 1335 Lee Street, Charlottesville, VA 22908, USA; Department of Biochemistry and Molecular Genetics, University of Virginia, PO Box 800733, Charlottesville, VA 22908, USA.
  • 3 Department of Biochemistry and Molecular Genetics, University of Virginia, PO Box 800733, Charlottesville, VA 22908, USA.
  • 4 Department of Radiation Oncology, University of Virginia, PO Box 800383, Charlottesville, VA 22908, USA.
  • 5 Department of Biology, University of Rochester, 434 Hutchison Hall, Rochester, NY 14627, USA.
  • 6 Center for Cell Signaling, University of Virginia, West Complex, 1335 Lee Street, Charlottesville, VA 22908, USA; Department of Biochemistry and Molecular Genetics, University of Virginia, PO Box 800733, Charlottesville, VA 22908, USA; Department of Radiation Oncology, University of Virginia, PO Box 800383, Charlottesville, VA 22908, USA.
  • 7 W. M. Keck Biomedical Mass Spectrometry Laboratory, University of Virginia, Pinn Hall, Room 1034, Charlottesville, VA 22908, USA.
  • 8 Center for Cell Signaling, University of Virginia, West Complex, 1335 Lee Street, Charlottesville, VA 22908, USA; Department of Biochemistry and Molecular Genetics, University of Virginia, PO Box 800733, Charlottesville, VA 22908, USA. Electronic address: [email protected].
PMID: 28525742 DOI: 10.1016/j.molcel.2017.04.028
Abstract

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.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-16106
    99.89%, PARP Inhibitor