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Vertebrate Nucleoplasmin and NASP: Egg Histone Storage Proteins with Multiple Chaperone Activities

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Vertebrate Nucleoplasmin and NASP: Egg Histone Storage Proteins with Multiple Chaperone Activities The FASEB Journal • Review Vertebrate nucleoplasmin and NASP: egg histone storage proteins with multiple chaperone activities Ron M. Finn,*,1 Katherine Ellard,*,1 José M. Eirín-López,† and Juan Ausió*,2 *Department of Biochemistry and Microbiology, University of Victoria, Victoria, British Columbia, Canada; and †Chromatin Structure and Evolution (CHROMEVOL) Group, Departamento de Biología Celular y Molecular, Universidade da Coruña, A Coruña, Spain ABSTRACT Recent reviews have focused on the taxa.—Finn, R. M., Ellard, K., Eirín-López, J. M., Ausió, J. structure and function of histone chaperones involved Vertebrate nucleoplasmin and NASP: egg histone storage in different aspects of somatic cell chromatin metabo- proteins with multiple chaperone activities. FASEB J. 26, lism. One of the most dramatic chromatin remodeling 4788–4804 (2012). www.fasebj.org processes takes place immediately after fertilization and is mediated by egg histone storage chaperones. ⅐ ⅐ ⅐ These include members of the nucleoplasmin (NPM2/ Key Words: chromatin phosphorylation embryogenesis nuclear autoantigenic sperm protein ⅐ cancer NPM3), which are preferentially associated with his- tones H2A-H2B in the egg and the nuclear autoanti- genic sperm protein (NASP) families. Interestingly, in In 1978, Ron Laskey coined the term “molecular addition to binding and providing storage to H3/H4 in chaperone” to describe the ability of nucleoplasmin to the egg and in somatic cells, NASP has been shown to assist in the formation of nucleosomes by preventing be a unique genuine chaperone for histone H1. This the aggregation of core histones with DNA (1). A review revolves around the structural and functional decade later, R. J. Ellis expanded on the “molecular roles of these two families of chaperones whose activity chaperone” concept to include proteins that assist in is modulated by their own post-translational modifica- the post-translational assembly of other protein com- tions (PTMs), particularly phosphorylation. Beyond plexes (2). Before chaperone functions were under- their important role in the remodeling of paternal stood, it was believed that proteins folded and arranged chromatin in the early stages of embryogenesis, NPM themselves into larger macromolecular complexes in a and NASP members can interact with a plethora of spontaneous, independent way, requiring little addi- proteins in addition to histones in somatic cells and tional assistance (3). However, over the past 4 decades, play a critical role in processes of functional cell the roles of protein chaperones have been clarified, alteration, such as in cancer. Despite their common and they are now known to play an integral part in the presence in the egg, these two histone chaperones formation of manifold cellular complexes. The term appear to be evolutionarily unrelated. In contrast to “chaperone” is now used to describe an immense and members of the NPM family, which share a common varied compendium of proteins in both eukaryotes and monophyletic evolutionary origin, the different types of prokaryotes that assist in the post-translational process- NASP appear to have evolved recurrently within different ing of proteins to ensure proper folding and protein complex formation. Nowhere is this more apparent in the context of a cell, than in the extensive and diverse Abbreviations: AML, acute myeloid leukemia; ASF1, anti- range of histone chaperones involved in the rapid silencing function 1; CAF-1, chromatin silencing factor 1; CCD, coiled-coiled domain; CENP-A, centromere protein A; assembly and disassembly of chromatin. DAXX, death-associated protein 6; DEK, Drosophila Eph ki- Chromatin is a vast, highly dynamic and yet remark- nase; DSB, double-strand break; HAT, histone acetyltrans- ably organized assemblage of DNA and proteins found ferase; Hif1, Hat1p interacting factor-1; HIRA, histone cell in all eukaryotic cells. It allows for the compaction of a cycle regulation defective homolog A; Hsp90, heat-shock large quantity of DNA into the small nucleus of a cell, protein 90 kDa; K , dissociation constant; NAP1, nucleosome d where it organizes and protects DNA through the assembly protein 1; NASP, nuclear autoantigenic sperm pro- tein; NES, nuclear export signal; NLB, nucleolus-like body; formation of higher-order chromatin structures. The NLP, nucleoplasmin-like protein; NLS, nuclear localization rearrangement of these higher-order chromatin struc- signal; NPM, nucleoplasmin; NPM1, nucleophosmin; NPM2, tures allows for rapid structural transitions in order to nucleoplasmin; NPM3, nucleophosmin/nucleoplasmin 3; PTM, post-translational modification; RD, replication-depen- dent; RI, replication-independent; SHNi-TPR, Sim3-Hif1- 1 These authors contributed equally to this work. NASP interrupted TPR; Sim3, silencing in the middle of the 2 Correspondence: Department of Biochemistry and Micro- centromere protein 3; sNASP, somatic NASP; SPR, surface biology, University of Victoria, Petch building, 258a, Victoria, plasmon resonance; tNASP, testes-specific NASP; TPR, tet- BC, Canada V8W 3P6. E-mail: [email protected] ratricopeptide repeats doi: 10.1096/fj.12-216663 4788 0892-6638/12/0026-4788 © FASEB adjust to a variety of genomic processes, such as DNA of embryogenesis. In addition, they participate in many replication, transcription, recombination, and repair. other aspects of nuclear metabolism. In particular, this The principal repeating unit of chromatin is the is the first comprehensive review on NASP, a member nucleosome, composed of a histone octamer contain- of the silencing in the middle of the centromere ing an H3/H4 tetramer and two H2A/H2B dimers, protein 3 (Sim3)–Hat1p-interacting factor-1 (Hif1)– around which 147 bp of DNA are wrapped in ϳ1.67 NASP-interrupted tetratricopeptide repeats (TPR) fam- left-handed superhelical turns (4). Nucleosomes form ily (SHNi-TPR family; also known as the N1/N2 family; “beads on a string” arrays composed of nucleosome ref. 17). Interestingly, in contrast to most of the histone core particles connected by varying lengths of linker chaperones characterized to date, NASP exhibits a DNA onto which linker histones (histone H1 and H5 unique ability to bind to linker histones of the H1 family) and other nonhistone chromatin-binding pro- family in addition to histones H3 and H4. teins are associated to construct higher-order chroma- tin structures (5–7). With the exception of particular regions of the genome undergoing specific genomic HISTONE CHAPERONES processes, such as actively transcribing genes or during DNA repair, for example, all DNA in a cell is assembled In somatic cells, extensive networks of histone chaper- into nucleosomes or similar structures. ones work synergistically to deposit core and linker The assembly and disassembly of nucleosomes must histones onto DNA, which results in the formation of occur in a stepwise fashion, as new histones are depos- nucleosomes and higher-order chromatin structures ited onto newly synthesized DNA or as old histones are (18–23). Histone chaperone research has primarily replaced by new histones and/or histone variants, focused on the characterization of processes involved in during the rest of the cell cycle. All of this is facilitated the stepwise addition of core histones during nucleo- through histone transport, deposition, eviction, and some formation in somatic cells, while less is known storage (8, 9). Such essential processes are often in- about the chaperones involved in chromatin remodel- duced and mediated by a number of ATP-dependent ing processes that take place following egg fertilization. chromatin remodeling complexes, nonhistone chroma- In the eggs of vertebrate organisms, the chaperone tin-associated proteins, post-translational modification responsible for the storage of H3/H4 and possibly H1 enzymes, and histone chaperones (10). The latter are is NASP (SHNi-TPR family) and for H2A/H2B is NPM often found interacting with the nucleosomes during family. This review will focus on these particular groups key cellular processes (11), and the loss of their chap- of histone chaperones, with particular emphasis on erone function can result in DNA damage, genomic Homo sapiens nucleophosmin (NPM1), nucleoplasmin instability, cell cycle arrest, or cell death (12–15). (NPM or NPM2), and nucleophosmin/nucleoplasmin To further underscore the importance of histone 3 (NPM3) and on the two primary Homo sapiens iso- chaperones in the rapid restructuring of nucleosomes, forms of NASP, testes-specific NASP (tNASP) and so- one has to consider that this assembly and disassembly matic NASP (sNASP). activity has to be accomplished accurately and in a Before newly synthesized histones can be incorpo- timely fashion in the context of intricate nucleosome rated into chromatin, they must first be produced in structures. These structures are highly stable complexes the cytoplasm and protected from protein degradation composed of Ͼ120 direct protein-DNA interactions and nonspecific interactions. In addition, appropriate and several hundred water- and ion-mediated interac- histone levels must be strictly regulated on a transla- tions (4, 16). In addition, it should be noted that tional and post-translational level to prevent genomic chromatin structure varies across the genome, depend- instability or abnormal chromatin structures (24). The ing on numerous factors, such as whether a gene is highly positive nature of histones can result in free being actively transcribed, or whether the region of histones binding nonspecifically to DNA, RNA,
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