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Nucleolar disruption ensures nuclear accumulation of p21 upon DNA damage

Neus Abella1, Sonia Brun, Maria Calvo

  • 1Departament de Biologia Cellular, Immunologia i Neurociencies, Institut d'Investigacions Biomèdiques August Pi i Sunyer, Facultat de Medicina, Universitat de Barcelona, Spain.

Traffic (Copenhagen, Denmark)
|March 25, 2010
PubMed

Insights

The protein p21 (cip1) accumulates in the nucleus and nucleolus after DNA damage, independent of ATR/ATM and p53 pathways. This nuclear and nucleolar accumulation is due to inhibited export, not just increased levels.

Area of Science:

  • Cell Biology
  • Molecular Oncology
  • DNA Damage Response

Background:

  • The protein p21 (cip1) has a dual role in oncogenesis, acting as a tumor suppressor in the nucleus and an oncogene in the cytoplasm.
  • Following DNA damage, p21 (cip1) levels rise and it accumulates in the nucleus to induce cell cycle arrest.

Purpose of the Study:

  • To investigate the mechanism of nuclear p21 (cip1) accumulation after DNA damage.
  • To determine if this accumulation is dependent on ataxia telangiectasia and Rad3 related (ATR)/ataxia telangiectasia mutated (ATM) and p53 signaling.
  • To elucidate the role of the nucleolus in p21 (cip1) localization after DNA damage.

Main Methods:

  • Analysis of p21 (cip1) localization in response to DNA damage.
  • Investigation of ATR/ATM and p53 independence.
  • Study of p21 (cip1) distribution within the nucleus and nucleolus.
  • Manipulation of nucleolar export using dominant-negative nucleophosmin.

Main Results:

  • Nuclear accumulation of p21 (cip1) post-DNA damage is independent of ATR/ATM and p53.
  • p21 (cip1) accumulates in both the nucleoplasm and the disrupted nucleolus.
  • Nucleolar accumulation occurs in distinct spherical structures.
  • A dynamic equilibrium exists between nucleoplasmic and nucleolar p21 (cip1), influenced by nuclear export inhibition.
  • Inhibition of ribosomal export leads to p21 (cip1) nuclear and nucleolar accumulation even without DNA damage.

Conclusions:

  • DNA damage triggers a p21 (cip1) nuclear and nucleolar accumulation response independent of ATR/ATM and p53.
  • A nucleolar export pathway for p21 (cip1) exists under normal conditions but is inhibited by DNA damage.
  • This inhibition of nucleolar export contributes to the observed nuclear and nucleolar p21 (cip1) accumulation.

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