A novel non-canonical PIP-box mediates PARG interaction with PCNA

Tanja Kaufmann, Anton Polyansky, Irina Grishkovskaya, Sebastian Kostrhon, Eva Kukolj, Karin Maria Olek, Sebastien Herbert, Etienne Beltzung, Karl Mechtler, Thomas Peterbauer, Josef Gotzmann, Lijuan Zhang, Markus Hartl, Bojan Zagrovic, Kareem Elsayad, Kristina Djinovic-Carugo, Dea Slade

Publications: Contribution to journalArticlePeer Reviewed

Abstract

Poly(ADP-ribose) glycohydrolase (PARG) regulates
cellular poly(ADP-ribose) (PAR) levels by rapidly
cleaving glycosidic bonds between ADP-ribose
units. PARG interacts with proliferating cell nuclear
antigen (PCNA) and is strongly recruited toDNAdamage
sites in a PAR- and PCNA-dependent fashion.
Here we identified PARG acetylation site K409 that
is essential for its interaction with PCNA, its localization
within replication foci and its recruitment to
DNA damage sites. We found K409 to be part of a
non-canonical PIP-box within the PARG disordered
regulatory region. The previously identified putative
N-terminal PIP-box does not bind PCNA directly but
contributes to PARG localization within replication
foci. X-ray structure and MD simulations reveal that
the PARG non-canonical PIP-box binds PCNA in a
manner similar to other canonical PIP-boxes and may
represent a new type of PIP-box. While the binding
of previously described PIP-boxes is based on hydrophobic
interactions, PARG PIP-box binds PCNA
via both stabilizing hydrophobic and fine-tuning electrostatic
interactions. Our data explain the mechanism
of PARG–PCNA interaction through a new
PARG PIP-box that exhibits non-canonical sequence
properties but a canonical mode of PCNA binding.
Original languageEnglish
Pages (from-to)9741-9759
Number of pages19
JournalNucleic Acids Research
Volume45
Issue number16
DOIs
Publication statusPublished - 19 Sept 2017

Austrian Fields of Science 2012

  • 106002 Biochemistry

Keywords

  • BINDING
  • DYNAMICS
  • GLYCOHYDROLASE
  • LOCALIZATION
  • POLY(ADP-RIBOSE)
  • POLYMERASES

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