Nucleolar Disruption Ensures Nuclear Accumulation of p21 upon DNA Damage

作者：Abella Neus; Brun Sonia; Calvo Maria; Tapia Olga; Weber Jason D; Berciano Maria T; Lafarga Miguel; Bachs Oriol; Agell Neus^*

来源：Traffic, 2010, 11(6): 743-755.

DOI：10.1111/j.1600-0854.2010.01063.x

• DNA damage
• NPM
• B23
• nuclear export
• nucleolus
• p21

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.

• 出版日期2010-6