Nucleophosmin: from structure and function to disease development

Abstract

Nucleophosmin (NPM1) is a critical cellular protein that has been implicated in a number of pathways including mRNA transport, chromatin remodeling, apoptosis and genome stability. NPM1 function is a critical requirement for normal cellular biology as is underlined in cancer where NPM1 is commonly overexpressed, mutated, rearranged and sporadically deleted. Consistent with a multifunctional role within the cell, NPM1 can function not only as a proto-oncogene but also as a tumor suppressor. The aim of this review is to look at the less well-described role of NPM1 in the DNA repair pathways as well as the role of NPM1 in the regulation of apoptosis and its mutation in cancers.

Keywords: Apoptosis; Cancer; DNA repair; Nucleophosmin 1.

Fig. 1

Overview of NPM1 functions within cells. NPM1 participate to many biological processes such as DNA repair, embryogenesis, likely by interacting with the chromatin, by binding to histones and other chromatin remodeling proteins. Importantly, NPM1 also promotes ribosome biogenesis

Fig. 2

a Superposition of NPM1 genomic structure and protein features. NPM1.1 and NPM1.3 are two splices variants resulting from the use of alternative codons. The two isoforms have different expression levels and localization. Ac Acidic domain, NES nuclear export signal, MB putative metal binding domain, NLS nucleus localization signal, NoLS Nucleolar localization signal. b Schematic structure of NPM proteins from human (not to scale). All proteins share a core, hydrophobic domain (blue) responsible for oligomerization and chaperone activity, followed by an acidic domain required for ribonuclease activity. A basic domain implicated in nucleic acid binding is common to NPM1 and NPM2, but absent in NPM3. Finally, only NPM1 exhibits a C-terminal aromatic stretch require for its nucleolar localization. In addition, NPM members harbor nuclear-localization signals (NLS), nucleolar-localization signal (NoLS), nuclear export signal (NES) and acidic clusters (a). c Simplified representation of the phylogenetic relationship within the NPM family. Inferred from [4]. The dendrogram reveals a clustering of sequences by type, rather than by species, and identifies NPM2 and NPM3 as polyphyletic groups

Fig. 3

a The crystal structure of the N-terminal oligomerization domain of NPM1 organized in a decamer, with two NPM1 pentameric rings stacked in a head-to-head fashion. Each NPM1 monomer is depicted in a different color. Structure derived from PDB data (PDB ID: 2P1B; [18]) visualized using Swiss PDB viewer. b Top view of a pentameric structure shown in a, showing the organization of monomers into a donut shaped ring. c Electrostatic potential map of a and b, showing an asymmetric distribution of charges, with negative charges (red) on the top surface of the pentamer and neutral (white) to slightly positive (blue) charges

Fig. 4

Regulation of apoptosis by NPM1. In unstressed cells, p14^ARF and NPM1 form a dimer in the nucleoli, allowing MDM2 to target p53 for proteasomal degradation. Following a stress, such as DNA damages, p14^ARF and NPM1 dissociate and relocate to the nucleus were they sequester MDM2, leading to the stabilization and activation of p53. p53 then induces the transcription of various genes involved in cell-cycle arrest, DNA repair and apoptosis

Fig. 5

Overview of NPM1 functions in various DNA damage response pathways. NPM1 has been shown to modulate the BER pathway as well as the translesion synthesis by modulating the levels of apurinic/apyrimidinic endonuclease 1 (APE1) and polymerase eta. In the absence of NPM1 or with the expression of non-phosphorylatable NPM1, double-strand break repair by homologous recombination fails to be completed, however the exact mechanism of NPM1 function in these pathway remain to be fully elucidated

Fig. 6

a Schematic structure of NPM1 chimeric proteins found in cancers. NPM1 is represented as in Fig. 2b. b Representation of the localization of wild-type NPM1, NPM1c+ and NPM1-ALK fusion protein in cancer. NPM1c+ (indicated by an asterisk) is cytoplasmic and can form dimers with NPM1 WT, retaining it in the cytoplasm. NPM1-ALK can dimerize and localize to the cytoplasm. Inversely, NPM1-ALK can form heterodimers with NPM1 WT, causing ALK dislocation into the nucleus (arrow). These cells shown both aberrant localization of ALK in the nucleus, and NPM1 in the cytoplasm