The Nucleolus Takes Control of Protein Trafficking Under Cellular Stress

Abstract

The nucleolus is a highly dynamic nuclear substructure that was originally described as the site of ribosome biogenesis. The advent of proteomic analysis has now allowed the identification of over 4500 nucleolus associated proteins with only about 30% of them associated with ribogenesis (1). The great number of nucleolar proteins not associated with traditionally accepted nucleolar functions indicates a role for the nucleolus in other cellular functions such as mitosis, cell-cycle progression, cell proliferation and many forms of stress response including DNA repair (2). A number of recent reviews have addressed the pivotal role of the nucleolus in the cellular stress response (1, 3, 4). Here, we will focus on the role of Nucleolin and Nucleophosmin, two major components of the nucleolus, in response to genotoxic stress. Due to space constraint only a limited number of studies are cited. We thus apologize to all our colleagues whose works are not referenced here.

Figure 1. Nucleoli protein trafficking in response to DNA damage

The nucleolus is depopulated of its protein content in response to a variety of cellular stress. Proteins are grouped according to the direction they are moving. Arrows indicate the direction of the proteins movement. The Werner protein helicase accumulates in intranuclear repair foci in response to camptothecin (CPT). NCL: Nucleolin, IR: Ionizing Radiation, TDP1: Tyrosyl DNA phosphodiesterase 1, PML: Promyelocytic Leukemia protein, MMC: Mitomycin C, PARP: poly(ADPribose) polymerase (4, 52) (53).

Figure 2. Schematic representation of potential NPM regulation of p53 in response to UV radiation

(A) Under normal conditions, ARF is retained in the nucleolus by its association with NPM and Topo1. (B) In response to UV radiation ARF dissociates from NPM and is release into the nucleoplasm where it associates with mdm2 and consequently stabilizes p53. (C) The dissociation of ARF from NPM frees NPM to interact with other proteins including p53 which represses its activation. ARF: Alternative Reading Frame, mdm2: murine double minute, NPM: nucleophosmin.

Figure 3

(A) Schematic representation of NPM domains and phosphorylation sites. OligoD: Oligomerization domain, Acidic domain including nuclear localization signal (NLS), HeteroD: heterodimerization domain, NBD: nucleic acid binding domain. ATM/ATR, CDK2/CyclinE and Cdc2 phosphorylation sites are indicated. (B) Dephosphorylation of NPM at Thr 199, 234 and 237 by PP1 facilitates NER. (C) Dephosphorylation of NPM at Ser 125 and possibly NCL at Ser145 by PP1 allows p53 phosphorylation at Ser15 in AT cells and facilitates G2 checkpoint in these cells. NPM: Nucleophosmin, PP1: Protein Phosphatase 1, NCL: Nucleolin, NER: Nucleotide Excision Repair. See text for details.