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MDM2 binds and ubiquitinates PARP1 to enhance DNA replication fork progression
ISSN
2211-1247
Date Issued
2022
Author(s)
Giansanti, Celeste
Manzini, Valentina
Dickmanns, Antje
Palumbieri, Maria Dilia
Sanchi, Andrea
Kienle, Simon Maria
Rieth, Sonja
Scheffner, Martin
Lopes, Massimo
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.
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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