MDM2 binds and ubiquitinates PARP1 to enhance DNA replication fork progression

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2022
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Giansanti, Celeste
Manzini, Valentina
Dickmanns, Antje
Dickmanns, Achim
Palumbieri, Maria Dilia
Sanchi, Andrea
Dobbelstein, Matthias
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Cell reports. Cell Press. 2022, 39(9), 110879. eISSN 2211-1247. Available under: doi: 10.1016/j.celrep.2022.110879
Zusammenfassung

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.

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570 Biowissenschaften, Biologie
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MDM2, PARP1, ubiquitin, DNA replication, replication fork reversal, RECQ1, PRIMPOL, p53, poly ADP ribose
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ISO 690GIANSANTI, Celeste, Valentina MANZINI, Antje DICKMANNS, Achim DICKMANNS, Maria Dilia PALUMBIERI, Andrea SANCHI, Simon Maria KIENLE, Sonja RIETH, Martin SCHEFFNER, Matthias DOBBELSTEIN, 2022. MDM2 binds and ubiquitinates PARP1 to enhance DNA replication fork progression. In: Cell reports. Cell Press. 2022, 39(9), 110879. eISSN 2211-1247. Available under: doi: 10.1016/j.celrep.2022.110879
BibTex
@article{Giansanti2022-05-31binds-57794,
  year={2022},
  doi={10.1016/j.celrep.2022.110879},
  title={MDM2 binds and ubiquitinates PARP1 to enhance DNA replication fork progression},
  number={9},
  volume={39},
  journal={Cell reports},
  author={Giansanti, Celeste and Manzini, Valentina and Dickmanns, Antje and Dickmanns, Achim and Palumbieri, Maria Dilia and Sanchi, Andrea and Kienle, Simon Maria and Rieth, Sonja and Scheffner, Martin and Dobbelstein, Matthias},
  note={Article Number: 110879}
}
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