OncogeneMar 11, 2014

Mdmx increases genome instability without involving p53 or Mdm2

Longevity & Aging Weekly Brief ↗PubMed ↗DOI ↗

Updated Apr 5, 2026

Abstract

In 13 different cancer types evaluated, 6-90% exhibited elevated Mdmx levels alongside inactivated p53.

Elevated Mdmx levels inhibited the repair of double-strand DNA breaks and induced chromosome and chromatid breaks, contributing to genome instability.
Mdmx impaired early DNA damage-response signaling, particularly affecting phosphorylation mediated by the ATM kinase.
Mdmx was found to associate with Nbs1 of the MRN DNA repair complex, with this interaction increasing upon DNA damage.
Increased levels of Mdmx also led to cellular transformation independent of p53.
All observed effects related to Mdmx occurred in cells lacking Mdm2 and did not depend on the Mdm2-binding domain of Mdmx.

Simplified

The oncogene Mdmx is overexpressed in many human malignancies, and together with Mdm2, negatively regulates the p53 tumor suppressor. However, a p53-independent function of Mdmx that impacts genome stability has been described, but this function is not well understood. In the present study, we determined that of the 13 different cancer types evaluated, 6-90% of those that had elevated levels of Mdmx had concurrent inactivation (mutated or deleted) of p53. We show elevated levels of Mdmx-inhibited double-strand DNA break repair and induced chromosome and chromatid breaks independent of p53, leading to genome instability. Mdmx impaired early DNA damage-response signaling, such as phosphorylation of the serine/threonine-glutamine motif, mediated by the ATM kinase. Moreover, we identified Mdmx associated with Nbs1 of the Mre11-Rad50-Nbs1 (MRN) DNA repair complex, and this association increased upon DNA damage and was detected at chromatin. Elevated Mdmx levels also increased cellular transformation in a p53-independent manner. Unexpectedly, all Mdmx-mediated phenotypes also occurred in cells lacking Mdm2 and were independent of the Mdm2-binding domain (RING) of Mdmx. Therefore, Mdmx-mediated inhibition of the DNA damage response resulted in delayed DNA repair and increased genome instability and transformation independent of p53 and Mdm2. Our results reveal a novel p53- and Mdm2-independent oncogenic function of Mdmx that provides new insight into the many cancers that overexpress Mdmx.

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Mdmx increases genome instability without involving p53 or Mdm2

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