Dysfunction of the MDM2/p53 axis is linked to premature aging
Davor Lessel, Danyi Wu, Carlos Trujillo, Thomas Ramezani, Ivana Lessel, Mohammad K. Alwasiyah, Bidisha Saha, Fuki M. Hisama, Katrin Rading, Ingrid Goebel, Petra Schütz, Günter Speit, Josef Högel, Holger Thiele, Gudrun Nürnberg, Peter Nürnberg, Matthias Hammerschmidt, Yan Zhu, David R. Tong, Chen Katz, George M. Martin, Junko Oshima, Carol Prives, Christian Kubisch
Davor Lessel, Danyi Wu, Carlos Trujillo, Thomas Ramezani, Ivana Lessel, Mohammad K. Alwasiyah, Bidisha Saha, Fuki M. Hisama, Katrin Rading, Ingrid Goebel, Petra Schütz, Günter Speit, Josef Högel, Holger Thiele, Gudrun Nürnberg, Peter Nürnberg, Matthias Hammerschmidt, Yan Zhu, David R. Tong, Chen Katz, George M. Martin, Junko Oshima, Carol Prives, Christian Kubisch
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Concise Communication Aging Genetics

Dysfunction of the MDM2/p53 axis is linked to premature aging

Abstract

The tumor suppressor p53, a master regulator of the cellular response to stress, is tightly regulated by the E3 ubiquitin ligase MDM2 via an autoregulatory feedback loop. In addition to its well-established role in tumorigenesis, p53 has also been associated with aging in mice. Several mouse models with aberrantly increased p53 activity display signs of premature aging. However, the relationship between dysfunction of the MDM2/p53 axis and human aging remains elusive. Here, we have identified an antiterminating homozygous germline mutation in MDM2 in a patient affected by a segmental progeroid syndrome. We show that this mutation abrogates MDM2 activity, thereby resulting in enhanced levels and stability of p53. Analysis of the patient’s primary cells, genome-edited cells, and in vitro and in vivo analyses confirmed the MDM2 mutation’s aberrant regulation of p53 activity. Functional data from a zebrafish model further demonstrated that mutant Mdm2 was unable to rescue a p53-induced apoptotic phenotype. Altogether, our findings indicate that mutant MDM2 is a likely driver of the observed segmental form of progeria.

Authors

Davor Lessel, Danyi Wu, Carlos Trujillo, Thomas Ramezani, Ivana Lessel, Mohammad K. Alwasiyah, Bidisha Saha, Fuki M. Hisama, Katrin Rading, Ingrid Goebel, Petra Schütz, Günter Speit, Josef Högel, Holger Thiele, Gudrun Nürnberg, Peter Nürnberg, Matthias Hammerschmidt, Yan Zhu, David R. Tong, Chen Katz, George M. Martin, Junko Oshima, Carol Prives, Christian Kubisch

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Figure 4

Functional consequences of the identified mutation in the patient’s cells.

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Functional consequences of the identified mutation in the patient’s cell...
(A) CBMN assays in LCLs. Effect of γ-irradiation (1 and 2 Gy) on the induction of micronuclei (MN) in control and IV:7 (left y axis) LCLs and on cell viability in the presence of CytB, indicated by the NDI (right y axis). Data represent 3 independent experiments. P = 0.2; 1 Gy: P = 0.0006; 2 Gy: P = 0.0001 (2-tailed Student’s t test). NT, nontreated cells. (B) Chromosomal stability in LCLs. Graph shows the mean number of aberrations per cell observed in 100 metaphases of an unaffected individual (Control LCLs) and the index patient (IV:7 LCLs). LCLs were left untreated or treated with 80 ng/ml MMC for 48 hours. Data represent 2 independent experiments. P values are relative to control LCLs for each treatment. #P = 0.0002 (2-sample Poisson tests). (C) Senescence phenotype of IV:7 fibroblasts. Control 1 and IV:7 fibroblasts at passage 28 (P28) were stained for β-gal. Original magnification ×20. (D) Protein levels of LMNB1 and actin in primary fibroblasts from an unaffected individual (Control 1) and the index patient IV:7 at passages 18 (both), 31 (control 1), and 27 (index patient).