MDM2 binds and ubiquitinates PARP1 to enhance DNA replication fork progression.

DNA / genetics DNA Damage DNA Primase / metabolism DNA Replication Tumor Suppressor Protein p53 / metabolism
CP: Molecular biology DNA replication MDM2 PARP1 PRIMPOL RECQ1 p53 poly ADP ribose replication fork reversal ubiquitin

Journal

Cell reports
ISSN: 2211-1247
Titre abrégé: Cell Rep
Pays: United States
ID NLM: 101573691

Informations de publication

Date de publication:
31 05 2022
Historique:
received: 29 11 2021
revised: 15 04 2022
accepted: 05 05 2022
entrez: 1 6 2022
pubmed: 2 6 2022
medline: 7 6 2022
Statut: ppublish

Résumé

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.

Identifiants

DOI: 10.1016/j.celrep.2022.110879 PMID: 35649362
pubmed: 35649362
pii: S2211-1247(22)00654-4
doi: 10.1016/j.celrep.2022.110879
pii:
doi:

Substances chimiques

Tumor Suppressor Protein p53 0
DNA 9007-49-2
DNA Primase EC 2.7.7.-

Types de publication

Journal Article Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

IM

Pagination

110879

Informations de copyright

Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.

Déclaration de conflit d'intérêts

Declaration of interests The authors declare no competing interests.

Auteurs

Celeste Giansanti (C)

Institute of Molecular Oncology, Göttingen Center of Molecular Biosciences (GZMB), University Medical Center Göttingen, Justus-von-Liebig-Weg 11, 37077 Göttingen, Germany.

Valentina Manzini (V)

Institute of Molecular Oncology, Göttingen Center of Molecular Biosciences (GZMB), University Medical Center Göttingen, Justus-von-Liebig-Weg 11, 37077 Göttingen, Germany.

Antje Dickmanns (A)

Institute of Molecular Oncology, Göttingen Center of Molecular Biosciences (GZMB), University Medical Center Göttingen, Justus-von-Liebig-Weg 11, 37077 Göttingen, Germany.

Achim Dickmanns (A)

Department of Molecular Structural Biology, Institute of Microbiology & Genetics, GZMB, Georg-August-University Göttingen, Justus-von-Liebig-Weg 11, 37077 Göttingen, Germany.

Maria Dilia Palumbieri (MD)

Institute of Molecular Cancer Research, University of Zurich, Winterthurerstrasse 190, 8057 Zurich, Switzerland.

Andrea Sanchi (A)

Institute of Molecular Cancer Research, University of Zurich, Winterthurerstrasse 190, 8057 Zurich, Switzerland.

Simon Maria Kienle (SM)

Department of Biology, University of Konstanz, 78457 Konstanz, Germany.

Sonja Rieth (S)

Department of Chemistry, University of Konstanz, 78457 Konstanz, Germany.

Martin Scheffner (M)

Department of Biology, University of Konstanz, 78457 Konstanz, Germany.

Massimo Lopes (M)

Institute of Molecular Cancer Research, University of Zurich, Winterthurerstrasse 190, 8057 Zurich, Switzerland.

Matthias Dobbelstein (M)

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.

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Classifications MeSH

questionsmedicales.fr › Acides nucléiques, nucléotides et nucléosides › Acides nucléiques › ADN › MDM2 binds and ubiquitinates PARP1 to enhance...
questionsmedicales.fr › Phénomènes génétiques › Altération de l'ADN › MDM2 binds and ubiquitinates PARP1 to enhance...
questionsmedicales.fr › Enzymes et coenzymes › Enzymes › Transferases › Phosphotransferases › Nucleotidyltransferases › RNA nucleotidyltransferases › DNA-directed RNA polymerases › DNA primase › MDM2 binds and ubiquitinates PARP1 to enhance...
questionsmedicales.fr › Phénomènes génétiques › Réplication de l'ADN › MDM2 binds and ubiquitinates PARP1 to enhance...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Phosphoprotéines › Protéine p53 suppresseur de tumeur › MDM2 binds and ubiquitinates PARP1 to enhance...