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p53 isoforms regulate premature aging in human cells

Oncogene volume 37, pages 2379–2393 (2018)Cite this article

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Abstract

Cellular senescence is a hallmark of normal aging and aging-related syndromes, including the premature aging disorder Hutchinson-Gilford Progeria Syndrome (HGPS), a rare genetic disorder caused by a single mutation in the LMNA gene that results in the constitutive expression of a truncated splicing mutant of lamin A known as progerin. Progerin accumulation leads to increased cellular stresses including unrepaired DNA damage, activation of the p53 signaling pathway and accelerated senescence. We previously established that the p53 isoforms ∆133p53 and p53β regulate senescence in normal human cells. However, their role in premature aging is unknown. Here we report that p53 isoforms are expressed in primary fibroblasts derived from HGPS patients, are associated with their accelerated senescence and that their manipulation can restore the replication capacity of HGPS fibroblasts. We found that in near-senescent HGPS fibroblasts, which exhibit low levels of ∆133p53 and high levels of p53β, restoration of Δ133p53 expression was sufficient to extend replicative lifespan and delay senescence, despite progerin levels and abnormal nuclear morphology remaining unchanged. Conversely, Δ133p53 depletion or p53β overexpression accelerated the onset of senescence in otherwise proliferative HGPS fibroblasts. Our data indicate that Δ133p53 exerts its role by modulating full-length p53 (FLp53) signaling to extend the replicative lifespan and promotes the repair of spontaneous progerin-induced DNA double-strand breaks (DSBs). We showed that Δ133p53 dominant-negative inhibition of FLp53 occurs directly at the p21/CDKN1A and miR-34a promoters, two p53 senescence-associated genes. In addition, Δ133p53 expression increased the expression of DNA repair RAD51, likely through upregulation of E2F1, a transcription factor that activates RAD51, to promote repair of DSBs. In summary, our data indicate that Δ133p53 modulates p53 signaling to repress progerin-induced early onset of senescence in HGPS cells. Therefore, restoration of ∆133p53 expression may be a novel therapeutic strategy to treat aging-associated phenotypes of HGPS in vivo.

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Acknowledgements

We thank Tom Misteli for kindly providing reagents and materials. We are grateful to Madaiah Puttaraju, who provided technical assistance with quantitative real-time PCR of progerin and wild-type lamin A. We would like to thank Dr. Ana Robles for critical reading of the manuscript. Confocal microscopy was supported by the National Cancer Institute. This research was supported by the Intramural Research Program of the NIH, NCI.

Funding

This work was funded by the National Cancer Institute, National Institutes of Health. B.V. was supported with project from Czech Science Foundation P206/12/G151 and project MEYS - NPS I - LO1413.

Author contributions

N.V.M., F.A., K.I., and D.L. performed the experiments. I.H. provided essential expertize and reagents. N.V.M., I.H., B.V., D.P.L. and C.C.H. coordinated the study and wrote the manuscript. C.C.H. was responsible for the overall study.

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Authors and Affiliations

  1. Laboratory of Human Carcinogenesis, National Cancer Institute, NIH, Bethesda, MD, USA

    Natalia von Muhlinen, Izumi Horikawa, Fatima Alam, Kazunobu Isogaya, Delphine Lissa & Curtis C. Harris

  2. Regional Centre for Applied and Molecular Oncology, Masaryk Memorial Cancer Institute, Brno, Czech Republic

    Borek Vojtesek

  3. Department of Microbiology, Tumor and Cell Biology (MTC), Karolinska Institutet, Stockholm, Sweden

    David P Lane

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  1. Natalia von Muhlinen
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Correspondence to Curtis C. Harris.

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von Muhlinen, N., Horikawa, I., Alam, F. et al. p53 isoforms regulate premature aging in human cells. Oncogene 37, 2379–2393 (2018). https://doi.org/10.1038/s41388-017-0101-3

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