MDM2 binds and ubiquitinates PARP1 to enhance DNA replication fork progression

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.

Automated summary

The MDM2 oncoprotein antagonizes p53 and sustains DNA replication fork progression, even in the absence of functional p53. This study demonstrates that MDM2 binds, inhibits, ubiquitinates, and destabilizes PARP1, resulting in accelerated fork progression. MDM2 also reduces fork reversal frequency, increases micronuclei occurrence, and exacerbates cell death, resembling the effects of PARP inhibition. These findings suggest that high MDM2 levels may represent a vulnerability of cancer cells.