2. Academic Validation
  3. MDM2 binds and ubiquitinates PARP1 to enhance DNA replication fork progression

MDM2 binds and ubiquitinates PARP1 to enhance DNA replication fork progression

  • Cell Rep. 2022 May 31;39(9):110879. doi: 10.1016/j.celrep.2022.110879.
Celeste Giansanti 1,  Valentina Manzini 1,  Antje Dickmanns 1,  Achim Dickmanns 2,  Maria Dilia Palumbieri 3,  Andrea Sanchi 3,  Simon Maria Kienle 4,  Sonja Rieth 5,  Martin Scheffner 4,  Massimo Lopes 3,  Matthias Dobbelstein 6
Affiliations

Affiliations

  • 1 Institute of Molecular Oncology, Göttingen Center of Molecular Biosciences (GZMB), University Medical Center Göttingen, Justus-von-Liebig-Weg 11, 37077 Göttingen, Germany.
  • 2 Department of Molecular Structural Biology, Institute of Microbiology & Genetics, GZMB, Georg-August-University Göttingen, Justus-von-Liebig-Weg 11, 37077 Göttingen, Germany.
  • 3 Institute of Molecular Cancer Research, University of Zurich, Winterthurerstrasse 190, 8057 Zurich, Switzerland.
  • 4 Department of Biology, University of Konstanz, 78457 Konstanz, Germany.
  • 5 Department of Chemistry, University of Konstanz, 78457 Konstanz, Germany.
  • 6 Institute of Molecular Oncology, Göttingen Center of Molecular Biosciences (GZMB), University Medical Center Göttingen, Justus-von-Liebig-Weg 11, 37077 Göttingen, Germany. Electronic address: mdobbel@uni-goettingen.de.
PMID: 35649362 DOI: 10.1016/j.celrep.2022.110879
Abstract

The MDM2 oncoprotein antagonizes the tumor suppressor p53 by physical interaction and ubiquitination. However, it also sustains the progression of DNA replication forks, even in the absence of functional p53. Here, we show that MDM2 binds, inhibits, ubiquitinates, and destabilizes poly(ADP-ribose) polymerase 1 (PARP1). When cellular MDM2 levels are increased, this leads to accelerated progression of DNA replication forks, much like pharmacological inhibition of PARP1. Conversely, overexpressed PARP1 restores normal fork progression despite elevated MDM2. Strikingly, MDM2 profoundly reduces the frequency of fork reversal, revealed as four-way junctions through electron microscopy. Depletion of RECQ1 or the primase/polymerase (PRIMPOL) reverses the MDM2-mediated acceleration of the nascent DNA elongation rate. MDM2 also increases the occurrence of micronuclei, and it exacerbates camptothecin-induced cell death. In conclusion, high MDM2 levels phenocopy PARP inhibition in modulation of fork restart, representing a potential vulnerability of Cancer cells.

Keywords

CP: Molecular biology; DNA replication; MDM2; PARP1; PRIMPOL; RECQ1; p53; poly ADP ribose; replication fork reversal; ubiquitin.

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