Nucleolar Disruption Ensures Nuclear Accumulation of p21 upon DNA Damage |
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Authors: | Neus Abella Sonia Brun Maria Calvo Olga Tapia Jason D Weber Maria T Berciano Miguel Lafarga Oriol Bachs Neus Agell |
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Institution: | 1. Departament de Biologia Cellular, Immunologia i Neurociencies, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Facultat de Medicina, Universitat de Barcelona, Spain;2. Unitat de Microscopia Confocal, Serveis Cientificotècnics, IDIBAPS, Universitat de Barcelona, Spain;3. Departamento de Anatomía y Biología Celular, Unidad de Biomedicina asociada al Instituto de Investigaciones Biomédicas (CSIC), Universidad de Cantabria, Santander, Spain;4. Department of Medicine, Division of Molecular Oncology, Washington University School of Medicine, St Louis, MO 63110, USA |
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Abstract: | p21cip1 is a protein with a dual function in oncogenesis depending mainly on its intracellular localization: tumor suppressor in the nucleus and oncogenic in the cytoplasm. After DNA damage, p21cip1 increases and accumulates in the nucleus to ensure cell cycle arrest. We show here that the nuclear accumulation of p21cip1 is not only a consequence of its increased levels but to a DNA damage cellular response, which is ataxia telangiectasia and Rad3 related (ATR)/ataxia telangiectasia mutated (ATM) and p53 independent. Furthermore, after DNA damage, p21cip1 not only accumulates in the nucleoplasm but also in the disrupted nucleolus. Inside the nucleolus, it is found in spherical structures, which are not a protrusion of the nucleoplasm. The steady‐state distribution of p21cip1 in the nucleolus resulted from a highly dynamic equilibrium between nucleoplasmic and nucleolar p21cip1 and correlated with the inhibition of p21cip1 nuclear export. Most interestingly, inhibition of ribosomal export after expressing a dominant‐negative mutant of nucleophosmin induced p21cip1 accumulation in the nucleus and the nucleolus in the absence of DNA damage. This proved the existence of a nucleolar export route to the cytoplasm for p21cip1 in control conditions that would be inhibited upon DNA damage leading to nuclear and nucleolar accumulation of p21cip1. |
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Keywords: | DNA damage NPM/B23 nuclear export nucleolus p21 |
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