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Aging and chronic DNA damage response activate a regulatory pathway involving miR-29 and p53

Alejandro P Ugalde1, Andrew J Ramsay, Jorge de la Rosa

  • 1Departamento de Bioquímica y Biología Molecular, Instituto Universitario de Oncología, Universidad de Oviedo, Oviedo, Spain.

The EMBO Journal
|April 28, 2011
PubMed

Insights

MicroRNAs (miRNAs), specifically the miR-29 family, are upregulated during aging and in response to DNA damage. This suggests a novel regulatory circuit involving miR-29, Ppm1d, and p53 that impacts aging processes.

Area of Science:

  • Molecular Biology
  • Genetics
  • Gerontology

Background:

  • Aging is a complex process impacting biological functions and increasing disease susceptibility.
  • MicroRNAs (miRNAs) are implicated in aging, but their specific roles remain largely unknown.
  • Zmpste24-deficient mice serve as a model for Hutchinson-Gilford progeria syndrome, offering insights into aging mechanisms.

Purpose of the Study:

  • To investigate the role of microRNAs (miRNAs) in aging.
  • To analyze miRNA expression profiles in Zmpste24-deficient mice and during normal aging.
  • To elucidate the regulatory mechanisms underlying miRNA involvement in aging and DNA damage response.

Main Methods:

  • Analysis of miRNA expression levels in Zmpste24(-/-) progeroid mice and normally aging mice.
  • Functional studies to determine the triggers and pathways regulating miR-29 expression.
  • Investigation of the p53-dependency of miR-29 transcriptional activation using p53(-/-) murine fibroblasts.
  • Assessment of miR-29's effect on Ppm1d phosphatase activity and subsequent p53 activity.

Main Results:

  • The miR-29 family of miRNAs is significantly upregulated in Zmpste24(-/-) progeroid mice and during normal mouse aging.
  • Transcriptional activation of miR-29 is induced by DNA damage and is dependent on the tumor suppressor protein p53.
  • miR-29 directly represses Ppm1d phosphatase, leading to enhanced p53 activity.
  • A novel regulatory circuit involving miR-29, Ppm1d, and p53 is identified.

Conclusions:

  • The miR-29 family plays a crucial role in the aging process and in response to DNA damage.
  • A novel p53-dependent regulatory pathway involving miR-29 and Ppm1d is activated during aging.
  • This regulatory circuitry offers potential targets for understanding and intervening in age-related decline and disease.

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