Nucleophosmin: from structure and function to disease development
© The Author(s) 2016
Received: 8 May 2016
Accepted: 16 August 2016
Published: 24 August 2016
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.
Gene organization and evolutionary history
NPM1 belongs to a histone chaperones family, the Nucleophosmin/nucleoplasmin (NPM) family, a group that comprises multiple major functional members (NPM1, NPM2, NPM3 and the invertebrate NPM-like), and can be found amongst all Metazoan . While this family is well characterized functionally, little is known about the evolution of these genes and proteins. At a glance, all members of the NPM family exhibit conserved structural motifs; a N-terminal core domain, an acidic domain and a nuclear localization signal, associated with a less conserved, disorganized C-terminus region (Fig. 2b) . Subsequently, crystallographic studies revealed a similar tertiary organization for NPM1 and NPM2 with monomers organized into pentameric donut-shaped complexes [6, 7].
As simplified in Fig. 2c, phylogenetic analysis revealed the late emergence of the NPM1 monophyletic clade while, in contrast, NPM2 and NPM3 lineages appear of polyphyletic origin, with mammalians and amphibians sequences clearly differentiated . Consistent with their shared expression profile, localization and direct physical interaction, NPM1 and NPM3 are the most closely related members of the family, suggesting functional constraints between the two proteins . Huang et al.  further suggest that NPM3 may have evolved following the loss of a nucleic acid binding domain of NPM1, and functions as an element regulating NPM1 RNA binding.
Interestingly, codon usage within the NPM gene family indicates a strong purifying selection, materialized by a high rate of silent mutations which significantly deviates from neutrality. The highly conserved organization of NPM proteins as pentamers further supports the hypothesis of a strong negative selection operating at the structural level. Interestingly, potential sites of post-translational modifications are also selectively constrained, being conserved not only at the protein level but also showing a preferred codon usage . Remarkably, these characteristics are shared with evolutionary features observed in histones, suggesting intertwined evolutionary history between the two families .
Despite being the most recent divergent NPM lineage, the functions of NPM1 are diverse and include roles in ribosome biogenesis [10, 11], mRNA processing , chromatin remodeling , embryogenesis , regulation of apoptosis and maintenance of genome stability.
Characteristic structural features of nucleophosmin
NPM1 structural architecture is well characterized by three distinct regions, onto which nucleolar and nuclear localization motifs, nucleic acids binding domains, oligomerization domains, histones binding regions, as well as a putative metal binding domain, have been mapped and described in detail [15–17] (Fig. 2a, b).
The NPM1 central region appears unstructured and is marked by the presence of highly acidic regions composed of strings of aspartic and glutamic acids (A1, A2 and A3). They provide long tracks of negatively charged residues, known to be involved in the binding to Histones H1, H3, H4, H2A and H2B, potentially by mimicking the charges of DNA and RNA [20, 21]. It also contains a nuclear localization signal.
The C-terminus of NPM1 is characterized by the presence of a basic, positively charged cluster of amino acids, immediately followed by a stretch of aromatic residues, providing an adequate platform allowing the binding to nucleic acids and ATP [16, 22]. These aromatic residues constitute an atypical nucleolar localization signal (NoLS), and their mutation are responsible for the unfolding and the aberrant NPM1 localization typical in acute myeloid leukemia (AML) cases.
Function of NPM1 in apoptosis
Although the best described function of NPM1 is in ribosome biogenesis, NPM1 also displays a critical role in regulating apoptosis. NPM1 expression levels have been implicated in controlling the cellular apoptotic response. In a variety of cell based models, several studies have demonstrated that down-regulation of NPM1 sensitizes cells to apoptosis, while increased levels of the protein protects against apoptosis [23–25]. In a disease setting, the balance between NPM1 expression and cell fate is demonstrated in hypoxia-driven cancers. For example, suppression of hypoxia-induced NPM1 expression promotes apoptosis whereas overexpression protects from hypoxia-mediated cell death . From a cancer perspective, elevated levels of NPM1 might promote malignant transformation by enabling cell survival.
In addition to p14ARF, MDM2 and possibly p53, NPM1 has been reported to bind PKB/Akt in order to modulate cell survival. In the nucleus, Akt binds NPM1 in response to growth factor stimulation to protect NPM1 against caspase-3-mediated proteolytic degradation and promote cell survival . Similarly, NPM1 stability is enhanced by interacting with erythroid differentiation-associated gene (EDAG), promoting acute myeloid leukemia (AML) cell survival . In another instance, the interaction of GAGE with NPM1 also enables NPM1 stability to promote resistance to interferon-γ-induced apoptosis .
NPM1 has also been portrayed as regulating cell fate by modulating both the intrinsic and extrinsic apoptosis pathways. During the intrinsic apoptotic response, p53 is required in the mitochondrial to enable cytochrome C release. Overexpression of NPM1 prevents the translocation of p53 from the nucleus to the mitochondria , suggesting that NPM1 may protect cells from apoptosis by reducing the mitochondrial level of p53. In acute promyelocytic leukemia cells expressing the NPM1-retinoic acid receptor α (NPM1-RAR) fusion protein, NPM1-RAR blocked TNF-induced extrinsic apoptosis by inhibiting signaling to activate caspase-3 and -8 . Similarly, mutant forms of NPM1 are indicated to impede apoptosis by directly inhibiting the proteolytic function of caspase-6 and -8 in the cytoplasm . Interestingly, in anaplastic large-cell lymphoma cells, the cytoplasmic fraction of the NPM1-ALK fusion protein is solely responsible for inducing apoptosis by engaging the DNA-damage response . These studies suggest, at least for the mutant or NPM1 fusion proteins, that the cytoplasmic fraction of NPM1 may be required to regulate the apoptotic pathways.
Role of NPM1 in the DNA repair response
Loss of NPM1 function has been shown to be associated with increased genome instability . Several studies have demonstrated the critical role of NPM1 in the maintenance of genome stability through its interaction with unduplicated centrosomes . The phosphorylation of NPM1 by CDK2/Cyclin E promotes the release of NPM1 from the centrosome during duplication; this represents an essential step for duplication to occur. However, during mitosis NPM1 re-associates with the centrosomes at the spindle bodies and appears to be controlling centrosome duplication . Indeed, depletion of NPM1 has been shown to promote genome instability (unaligned chromosomes, micronuclei) [44, 45]. In mice, the chromosomal instability associated with NPM1 depletion partially explains the embryonic lethality .
DNA double-strand breaks (DSB) are the most destructive and genotoxic lesions encountered by cells and as such complex cascades have evolved to sense, signal and repair these breaks. DNA DSBs can then be repaired by two pathways, homologous recombination (HR) and non-homologous end-joining (NHEJ) (reviewed in ). HR utilizes a sister chromatid as a template for repair and therefore can only be performed in the late S-phase and G2 phases of the cell cycle. In contrast, NHEJ can occur in any phase of the cell cycle and involves a less complex method of ligating the two DNA ends together. As overhanging DNA may be resected during this method, NHEJ is generally known as the more error-prone mechanism of DNA DSB repair. In the HR process, DSBs are detected and signaling pathways are initiated by the ATM/ATR kinases, promoting the recruitment of repair proteins, including nucleases that resect DNA with a 5′–3′ polarity. This resection generates stretches of single stranded DNA, which invade into a sister chromatid, allowing it to act as a template for polymerase-mediated extension of the invading strand. Following this extension and re-ligation of DNA strands this reaction then yields two intact and identical DNA molecules .
Thus far, NPM1 has only been implicated in homologous recombination (HR). Following DNA double-strand break induction, NPM1 is recruited from the nucleolus into the nucleoplasm and binds to the chromatin . NPM1 is phosphorylated at Threonine 199 by the cyclin-dependent kinases CDK1 and CDK2 during the cell cycle . A subsequent study showed that following induction of DNA double-strand breaks by ionizing irradiation, NPM1 phosphorylated on threonine 199 localizes to sites of DNA double-strand breaks, colocalizing with other DNA repair proteins such as γH2AX and BRCA1 . Phosphorylated NPM1 is recruited to sites of DNA marked by K63-linked ubiquitin conjugates in a process dependent upon the ubiquitin ligases RNF8 and RNF168. Depletion of NPM1 or expression of non-phosphorylatable NPM1 (T199A) leads to persistence of Rad51 foci suggesting that repair of DNA DSBs is not completed. This is further supported by the detection of increased DNA lesions in cells expressing NPM1 T199A. In contrast, cellular survival following ionizing radiation was not significantly affected . Another study also analyzed γH2AX and Rad51 foci kinetics and showed that DNA damage also persisted in NPM1-null mouse embryonic fibroblast (MEF) cells . Like the studies in human cells, NPM1-null MEFs also exhibited increased DNA lesions and a modest decrease in cellular survival following ionizing radiation. An anti-cancer agent, YTR107, was also shown to act by binding to NPM1 and altering its function. YTR107 inhibits DNA repair and radiosensitizes cells in an NPM1-dependent process . In light of the above it is clear that NPM1 has a role in DNA DSB repair, however much is still to be elucidated about the exact mechanism of its function in these pathways (Fig. 5).
Following exposure of cells to agents such as UV, DNA lesions may cause replication forks to stall as the replicative polymerases are unable to bypass the UV-induced bulky lesions. In order for these stalled replication forks to be restarted, they can be repaired by a form of HR or be bypassed in a mechanism known as translesion synthesis (TLS, reviewed in , Fig. 5). A recent study identified NPM1 as a key player of the TLS pathway . This process enables switching of the DNA polymerase to a low fidelity DNA polymerase that can replicate the DNA across the lesion. NPM1 regulates TLS by binding to and protecting DNA Polymerase Eta (POLH, polη) from proteosomal degradation promoting its role in TLS. The mutated NPM1 (NPM1c+, found in 30 % of AML cases) was found to result in increased degradation of polη, perhaps explaining the improved prognosis in AML patients with NPM1 mutations .
In addition to its role in DNA double-strand break repair and translesion synthesis, NPM1 has also been shown to respond to DNA lesions induced by UV light. The alterations to nucleotides caused by UV irradiation are repaired by the nucleotide excision repair pathway, a process that is dependent upon the PCNA homo-trimer (reviewed in ). The levels of NPM1 protein were shown to increase following cellular exposure to UV . Exogenous overexpression of NPM1 was also found to increase cellular survival and DNA repair capacity following UV irradiation. Supporting a role for NPM1 in nucleotide excision repair (NER), it was found to transcriptionally regulate the crucial NER protein PCNA . Following UV irradiation, dephosphorylation of NPM1 on Threonine 199, 234 and 237 residues occurs in a PP1β-dependent manner. Dephosphorylation of these sites on NPM1 enhances the interaction between NPM1 and the retinoblastoma tumor suppressor protein (pRB), which then allows the release of E2F1 from pRB. E2F1 subsequently functions to transcriptionally activate several downstream DNA repair genes, including XPC, DDB2 and RPA14, facilitating DNA repair .
Oxidative damage to DNA is caused predominantly by normal cellular metabolism and is repaired by the base excision repair pathway (BER reviewed in ). NPM1 has been shown to modulate the BER pathway through control of the apurinic/apyrimidinic endonuclease 1 (APE1) protein levels and modulation of the AP-site incision activity of APE1, which is required for base excision repair (Fig. 5) [58–60]. Several nucleolar proteins involved in BER were also mislocalised in NPM1-deficient cells, including APE1, Fen1 and LigI . NPM1 was also found to belong to a complex containing several BER proteins, including APE1, Fen1, Polβ and LigI [62, 63].
NPM1 and cancer
Patients with NPM1 mutations proved to have a better outcome with increased complete remission and improved overall survival . However, within this group of patients, the antigen expression pattern of HLADR(+) CD34(+) CD7(+) is associated with poor prognosis . NPM1c+ has been shown to result in microRNAs deregulation , and a recent in vitro study established that NPM1c+ could enhance leukemia cells adhesion, migratory and invasive potential through MEK/ERK activation . Notably, NPM1 mutation in a knock-in mouse model resulted in AML initiation [72, 73], and studies on MEFs have shown that NPM1 mutation results in p14ARF destabilization  and c-Myc stabilization .
In anaplastic large-cell lymphoma (ALCL), NPM1 fusion with anaplastic lymphoma receptor tyrosine kinase (ALK) can be found in 85 % of the ALK+ ALCL, this results in the expression of a chimeric oncogenic protein formed by the C-terminus of NPM1 and the kinase domain of ALK (Fig. 6a) [64, 76]. In these cells both NPM1 and ALK exhibits aberrant localization. Further, dimerization of NPM1-ALK leads to a constitutive activation of the ALK kinase (Fig. 6b) .
Chimeric proteins between NPM1 and the retinoic acid receptor-α gene (RARα) or between NPM1 and the myelodysplasia/myeloid leukemia factor 1 (MLF1) have also been reported in rare cases of leukemia (Fig. 6a) [77, 78].
Besides leukemia, involvement of NPM1 has also been reported in several solid cancers. Overall, NPM1 overexpression is linked to high grade tumors and poor prognosis, as observed in brain glioblastoma , oral squamous cell carcinoma , non-small cells lung cancer (NSCLC) , hepatocellular carcinomas (HCC) , colon cancer [82–84], ovarian cancer [62, 85], and endometrial carcinoma . A higher level of NPM1 has also been observed in prostate cancer, when compared to normal tissue [87, 88], promoting cells growth and invasiveness . In bladder cancer, high levels of NPM1are not associated with tumor grade, but with cancer progression, recurrence, and poor prognosis . NPM1 overexpression has also been reported in thyroid cancer , with thyroid cancer cell lines showing NPM1 mislocalization in the absence of the mutations observed in AML patients .
However, low levels of NPM1 have also been observed in some cancers, such as gastric cancers (mRNA and protein) compared to normal tissue . In breast cancer, low NPM1 levels are also associated with poor outcome, independently of the molecular subtype, with granular staining of NPM1 correlating with poor prognosis .
Since NPM1 is overexpressed in many types of cancer and because of its role in genome stability, it could be a potential target for new cancer therapy strategies. Different molecules have been trialed to induce cell death by destabilizing NPM1 [95–98] or inhibiting its interaction with other DNA repair proteins . Recent studies have focused on combining NPM1 inhibition with a DNA damaging agent, for instance ionizing radiation [51, 100], or a cytotoxic drug . Other strategies are aiming specifically at NPM1c+ itself , or in combination with damage induction by increasing oxidative stress in cells [103–106].
As summarized here, NPM1 plays multiple roles within human cells while the best documented is in RNA transport and ribosome biogenesis, it is clear that NPM1 also plays a critical role in the regulation of apoptosis and in the maintenance of genomic homeostasis.
Genome instability is one of the underlying causes of cellular transformation and cancer development. Once a cancer does form, genome instability becomes a common feature seen as a universal hallmark of all cancers . This instability provides the cancer the ability to evolve and adapt to the environment in which it is located; further, defects in the apoptosis pathways allow the cancer cell to cope and survive with levels of genetic instability that would normally induce cell death.
Given the critical role NPM1 plays in genome stability and apoptosis it is hardly surprising that NPM1 dysfunction is a frequent feature in cancers. Indeed, as evidence of NPM1 function in DNA repair pathways increases, it explains at least in part the genetic instability associated with cancers such as AML. Further, NPM1 deregulation or mutation will suppress the ability of that cell to respond to apoptotic stimuli, allowing for the tolerance of the genetic instability. Consistent with a role in genetic instability and specifically the repair of double-strand DNA breaks we see that AML patients with a mutated NPM1 have a >2 fold higher odds of achieving complete remission as compared to patients with a wild type NPM1 . NPM1 in cancer is most strikingly highlighted in acute myeloid leukemia where approximately 30 % of patients will have a mutation or fusion event implicating NPM1.
Despite the importance of NPM1 in genome stability it is clear that we do not fully understand how NPM1 functions in the repair of DNA damage. We know that NPM1 moves to sites of double-strand DNA breaks within the genome, but we do not yet understand how NPM1 functions at those break sites. We do not know if NPM1 binds to nucleic acids at those sites or if it is involved in remodeling chromatin. It is clear, however, that understanding how NPM1 participates in DNA repair and genome stability will help to delineate the role of NPM1 in both normal and cancerous cells. This will perhaps provide insights into why NPM1 dysfunction is a marker of drug and radiation sensitivities.
protein kinase B
anaplastic lymphoma receptor tyrosine kinase
acute myeloid leukemia
apurinic/apyrimidinic endonuclease 1
ataxia telangiectasia mutated protein
ataxia telangiectasia and Rad3 related protein
breast cancer 1
damage-specific DNA binding protein 2
E2F transcription factor 1
erythroid differentiation-associated gene
mouse double minute 2 homolog
mouse embryonic fibroblast
myelodysplasia/myeloid leukemia factor 1
nucleotide excision repair
nucleolar localisation signal
proliferating cell nuclear antigen
protein kinase B
retinoic acid receptor α
ring finger protein1
replication protein A
translesion DNA synthesis
tumor necrosis factor
xeroderma pigmentosum, complementation group C
JKB, NP, MNA, DB, EB, KJO and DJR wrote the manuscript. All authors read and approved the final manuscript.
The authors declare that they have no competing interests.
This work was supported by a NHMRC project Grant (1066550), an ARC project Grant (D.J.R, DP 120103099) and by a Queensland Health Senior Clinical Research Fellowship (K.J.O.). M.A. holds a NHMRC Early Career Fellowship (1091589). E.B. is supported by an Advance Queensland Research Fellowship.
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