NIPA Targets Nuclear Cyclin B1 in a Cell-Cycle Dependent Manner.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 79-79
Author(s):  
Florian C. Bassermann ◽  
Christine von Klitzing ◽  
Silvia Kluempen ◽  
Ren-Yuan Bai ◽  
Tao Ouyang ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cyclin B1 ◽  
S Phase ◽  
Cyclin B ◽  
Nuclear Accumulation ◽  
Dependent Manner ◽  
Checkpoint Control ◽  
Mitotic Entry ◽  
F Box Protein ◽  
Constitutively Active

Abstract Ubiquitin-mediated destruction of regulatory proteins marks the vital means of controlling cell cycle progresssion. The E3 ubiquitin-ligases are prominent in this process, as they allow the transfer of ubiquitin to the target protein and mediate substrate binding specificity. Recently, a new class of E3 ligases referred to as SCF complexes has been identified that consists of four subunits:SKP1, Cul1, Roc1 and an F-box protein, the latter of which determines substrate specifity. We previously reported the cloning of NIPA (nuclear interaction partner of ALK) in complex with constitutively-active oncogenic fusions of ALK, which contribute to the development of certain lymphomas and sarcomas. Subsequently we characterized NIPA as a human F-box protein that determines a novel SCF complex (SCFNIPA) whose cell cycle regulated activity is restricted to interphase to allow for substrate expression at G2/M and mitosis. Phosphorylation of NIPA in late S-phase was found to be the underlying mechanism of SCFNIPA inactivation. We have now identified the key mitotic regulator cyclin B1 to serve as the relevant substrate of the SCFNIPA complex. This targeting process is restricted to interphase and directed towards the nuclear pool of cyclin B1. Inactivation of NIPA by siRNAs results in nuclear accumulation of cyclin B1 in interphase and an elevation of cells in S-phase and mitosis. In contrast, expression of a phosphorylation deficient NIPA mutant that retains constitutive SCFNIPA activity throughout the cell cycle arrests cells at early prophase thus delaying mitotic entry. Both effects are likely attributable to either cyclin B1 accumulation in the case of NIPA inactivation by siRNA or untimely cyclin B degradation at G2/M upon expression of the constitutively active SCFNIPA complex. Cyclin B1 is physiologically kept cytoplasmic during interphase and premature nuclear accumulation has been associated with untimely mitotic entry, loss of checkpoint control and genomic instability. Our data provides a mechanism to inhibit premature nuclear accumulation of cyclin B1 in the mammalian cell cycle. NIPAs association with NPM-ALK of ALCL has been shown to be associated with NIPA phosphorylation and thus to the inactivation of the SCFNIPA complex. The mechanism described above may therefore provide a framework for understanding how this oncogene interferes with the physiologic regulation of cyclin B - a potential mechanism by which NPM-ALK transforms hematopoietic cells.

Inactivation of NIPA Results in Premature Mitotic Entry and Subsequent Mitotic Catastrophe.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 1364-1364
Author(s):  
Florian C. Bassermann ◽  
Silvia Muench ◽  
Christine von Klitzing ◽  
Stephan W. Morris ◽  
Christian Peschel ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Nuclear Interaction ◽  
Cyclin B1 ◽  
Mitotic Checkpoint ◽  
Current Data ◽  
Mitotic Catastrophe ◽  
Cycle Phase ◽  
E3 Ligases ◽  
Mitotic Entry ◽  
F Box Protein

Abstract Ubiquitin-mediated destruction of regulatory proteins marks a vital means of controlling cell cycle progresssion. The E3 ubiquitin-ligases are prominent in this process as they determine specificity of the ubiquitination process and thus regulate proteasomal degradation of target proteins. Recently, a class of E3 ligases referred to as SCF complexes has been identified. The substrate binding specifity within this class of E3 ligases is mediated by a class of molecules termed F-box proteins. We previously reported the cloning of NIPA (nuclear interaction partner of ALK) in complex with constitutively-active oncogenic fusions of ALK, which contribute to the development of certain lymphomas and sarcomas. Subsequently we characterized NIPA as a human F-box protein that defines an oscillating ubiquitin ligase (SCF-NIPA) which targets nuclear cyclin B1 in interphase. We have now determined the consequence of inactivating NIPA with regard to cell cycle regulation using an RNAi approach. Kinetic analysis of cell cycle phase transition times revealed a premature onset of Cdk1/cyclin B1 kinase activity and early mitotic entry in cells treated with NIPA siRNA. Cyclin B1 was shown to accumulate within the nucleus in these cells correlative to a reduced ubiquitination activity of the SCF-NIPA complex. Subsequent to premature mitotic entry, NIPA inactivated cells arrested in prometaphase and mitotic catastrophe was observed thereafter. We searched for relevant proteins involved in this process and found Survivin, a member of the inhibitor of apoptosis proteins (IAP) to be strongly downregulated in NIPA siRNA treated cells. Survivin has been shown to function as a mitotic checkpoint molecule that induces mitotic catastrophe subsequent to aberant mitosis when inactivated or downregulated. While the precise functional relationship between Survivin and NIPA is still under investigation, the current data distinguishes NIPA as a central molecule in timing mitotic entry. Given this function, NIPA directly influences the fidelity of DNA replication and segregation. Interference with NIPA function may therefore be an oncogenic principle that favours genomic instability in tumor cells.

NIPA Checkpoint Control In Oncogenic Transformation Is Dependent on p53

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 4178-4178
Author(s):  
Anna Lena Illert ◽  
Hiroyuki Kawaguchi ◽  
Corinna Albers ◽  
Melanie Sickinger ◽  
Ulrich Keller ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cyclin B1 ◽  
Conditional Knockout ◽  
Substantial Contribution ◽  
Dependent Manner ◽  
Checkpoint Control ◽  
Oncogenic Transformation ◽  
Wild Type ◽  
Focus Formation ◽  
Wild Type Mefs

Abstract Abstract 4178 The regulated oscillation of protein expression is an essential mechanism of cell cycle control. The SCF class of E3 ubiquitin ligases is involved in this process by targeting cell cycle regulatory proteins for degradation by the proteasome, with the F-Box subunit of the SCF specifically recruiting a given substrate to the SCF core. We previously reported the cloning of NIPA (Nuclear Interaction Partner of ALK) in complex with constitutively active oncogenic fusions of ALK, which contributes to the development of lymphomas and sarcomas. Subsequently we characterized NIPA as a F-Box protein that defines an oscillating ubiquitin E3 ligase targeting nuclear cyclin B1 in interphase thus contributing to the timing of mitotic entry. Using a conditional knockout strategy we inactivated the gene encoding NIPA. NIPA-deficient animals are viable, but sterile due to a block of spermatogenesis. Moreover, our studies demonstrate that loss of NIPA has no substantive effect on the physiological cell cycle progression of primary MEFs indicating that this cell cycle checkpoint is inactive under optimal proliferation conditions. Interestingly, NIPA checkpoint control can be unmasked by oncogenic transformation by c-Myc. Here we show that transformed focus formation assays revealed highly significant differences in c-Myc-induced transformation in NIPA-deficient and wild-type MEFs. c-Myc transduction caused a pronounced upregulation of cyclin-B in NIPA-null MEFs, which was completely reversible by ectopic NIPA expression. The increased cyclin-B1 expression after c-Myc transduction in the absence of NIPA has considerable functional consequences for the cells: Focus formation ability of c-Myc-infected Nipa-/- MEFs was greatly reduced in comparison to wild-type MEFs (24.6% vs. 100%). Moreover, c-Myc expression caused 12.8% apoptotic subG1 cells in wild-type MEFs, whereas Nipa-/- MEFs were more affected by c-Myc-induced apoptosis (22.45%). Next, we sought to know, whether increased apoptosis in Nipa-deficient c-Myc transduced MEFs is dependent on a functional p53-Axis. Therefore, Nipa-wildtype and knockout MEFs were first infected with a retroviral Supernatant encoding for a p53Mir- and thereafter with the oncogene c-Myc. Interestingly the effect of Nipa knockout on c-Myc-mediated oncogenic transformation was totally abolished by the knock-down of p53. We observed no differences in focus formation ability or growth behaviour in Nipa-/- MEFs with inactivated p53 in comparison to wildtype cells, suggesting the importance of functional p53 in Nipa-induced cell death. Taken together, our data demonstrate that NIPA is required for efficient c-Myc transformation in a p53-dependent manner. Moreover, our results highlight the functional importance of the NIPA-p53 axis in cell cycle regulation and suggest that deregulation of the protein provides a substantial contribution during the process of tumorigenesis. Disclosures: No relevant conflicts of interest to declare.

Nuclear accumulation of ZFP36L1 is cell cycle-dependent and determined by a C-terminal serine-rich cluster

2020 ◽  
Vol 168 (5) ◽  
pp. 477-489
Author(s):  
Yuki Matsuura ◽  
Aya Noguchi ◽  
Shunsuke Sakai ◽  
Naoto Yokota ◽  
Hiroyuki Kawahara
Keyword(s):  
Cell Cycle ◽  
Nuclear Localization ◽  
Rna Binding ◽  
S Phase ◽  
Nuclear Accumulation ◽  
Protein Accumulation ◽  
Dependent Manner ◽  
Rich Cluster ◽  
G2 Phase ◽  
Cycle Dependent

Abstract ZFP36L1 is an RNA-binding protein responsible for mRNA decay in the cytoplasm. ZFP36L1 has also been suggested as a nuclear-cytoplasmic shuttling protein because it contains a potential nuclear localization signal and a nuclear export signal. However, it remains unclear how the nuclear localization of ZFP36L1 is controlled. In this study, we provide evidence that the nuclear accumulation of ZFP36L1 protein is modulated in a cell cycle-dependent manner. ZFP36L1 protein accumulation in fractionated nuclei was particularly prominent in cells arrested at G1-/S-phase boundary, while it was downregulated in S-phase cells, and eventually disappeared in G2-phase nuclei. Moreover, forced nuclear targeting of ZFP36L1 revealed marked downregulation of this protein in S- and G2-phase cells, suggesting that ZFP36L1 can be eliminated in the nucleus. The C-terminal serine-rich cluster of ZFP36L1 is critical for the regulation of its nuclear accumulation because truncation of this probable disordered region enhanced the nuclear localization of ZFP36L1, increased its stability and abolished its cell cycle-dependent fluctuations. These findings provide the first hints to the question of how ZFP36L1 nuclear accumulation is controlled during the course of the cell cycle.

Control of Meiotic and Mitoic Progression by the F-Box Protein NIPA In Vivo.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 1118-1118
Author(s):  
Anna L. Illert ◽  
Hiroyuki Kawaguchi ◽  
Letitia Quintanilla-Fend ◽  
Florian Bassermann ◽  
Christine von Klitzing ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Germ Cells ◽  
Cyclin B1 ◽  
Conditional Knockout ◽  
Regulatory Function ◽  
Histological Evaluation ◽  
Mitotic Entry ◽  
Germ Cell Differentiation ◽  
F Box Protein

Abstract The regulated oscillation of protein expression is an essential mechanism of cell cycle control. The SCF class of E3 ubiquitin ligases is involved in this process by targeting cell cycle regulatory proteins for degradation by the proteasome, with the F-Box subunit of the SCF specifically recruiting a given substrate to the SCF core. We previously reported the cloning of NIPA (Nuclear Interaction Partner of ALK) in complex with constitutively active oncogenic fusions of ALK, which contributes to the development of lymphomas and sarcomas. Subsequently we characterized NIPA as a F-Box protein (FBP) that defines an oscillating ubiquitin E3 ligase targeting nuclear cyclin B1 in interphase thus contributing to the timing of mitotic entry. Using a conditional knockout strategy we inactivated the gene encoding the FBP NIPA to determined the consequences of NIPA deletion in vivo. The targeting construct was designed to flank exon 1 and 2 of the NIPA gene with loxP-sites. Deletion of this region was obtained by crossing the floxed mice to a cre-transgenic mouse strain expressing cre ubiquitously. NIPA deficiency did not affect the viability of NIPA −/− animals. Mating of heterozygotes yielded NIPA +/+, NIPA +/− and NIPA −/− offspring approximately at the expected Mendelian ratio. Although copulatory behavior was normal and vaginal plugs were produced, NIPA-deficient animals have a fertility defect. 100% of the tested NIPA −/− males and 60% of NIPA −/− females never produced progeny with young fertile wild-type mice. Interestingly, histological evaluation showed progressive testis atrophy in NIPA −/− males. Further analyses indicate a block in germ cell differentiation at the stage of meiotic prophase, no spermatides or spermatozoa were observed in NIPA-deficient animals. High levels of nuclear cyclin B1, a previously reported NIPA substrate, were present in NIPA-deficient germ cells. Furthermore, inactivation of NIPA leads to premature mitotic entry and subsequent mitotic catastrophe and TUNEL positive apoptosis in germ cells. Long-term studies of NIPA deficient mice may display a potential role of NIPA in tumor development. Since we found the most striking phenotype in high proliferating germ cells our results strongly confirm the cell cycle regulatory function of NIPA.

scholarly journals A protein synthesis-dependent increase in E2F1 mRNA correlates with growth regulation of the dihydrofolate reductase promoter.

1993 ◽  
Vol 13 (3) ◽  
pp. 1610-1618 ◽  
Author(s):  
J E Slansky ◽  
Y Li ◽  
W G Kaelin ◽  
P J Farnham
Keyword(s):  
Cell Cycle ◽  
Protein Synthesis ◽  
Phase Boundary ◽  
Dihydrofolate Reductase ◽  
Transcription Initiation ◽  
Growth Regulation ◽  
Cellular Proliferation ◽  
Protein S ◽  
S Phase ◽  
Dependent Manner

Enhanced expression of genes involved in nucleotide biosynthesis, such as dihydrofolate reductase (DHFR), is a hallmark of entrance into the DNA synthesis (S) phase of the mammalian cell cycle. To investigate the regulated expression of the DHFR gene, we stimulated serum-starved NIH 3T3 cells to synchronously reenter the cell cycle. Our previous results show that a cis-acting element at the site of DHFR transcription initiation is necessary for serum regulation. Recently, this element has been demonstrated to bind the cloned transcription factor E2F. In this study, we focused on the role of E2F in the growth regulation of DHFR. We demonstrated that a single E2F site, in the absence or presence of other promoter elements, was sufficient for growth-regulated promoter activity. Next, we showed that the increase in DHFR mRNA at the G1/S-phase boundary required protein synthesis, raising the possibility that a protein(s) lacking in serum-starved cells is required for DHFR transcription. We found that, similar to DHFR mRNA expression, levels of murine E2F1 mRNA were low in serum-starved cells and increased at the G1/S-phase boundary in a protein synthesis-dependent manner. Furthermore, in a cotransfection experiment, expression of human E2F1 stimulated the DHFR promoter 22-fold in serum-starved cells. We suggest that E2F1 may be the key protein required for DHFR transcription that is absent in serum-starved cells. Expression of E2F also abolished the serum-stimulated regulation of the DHFR promoter and resulted in transcription patterns similar to those seen with expression of the adenoviral oncoprotein E1A. In summary, we provide evidence for the importance of E2F in the growth regulation of DHFR and suggest that alterations in the levels of E2F may have severe consequences in the control of cellular proliferation.

Intracellular nickel accumulation induces apoptosis and cell cycle arrest in human astrocytic cells

Metallomics ◽  
2020 ◽  
Author(s):  
Ruedeemars Yubolphan ◽  
Suttinee Phuagkhaopong ◽  
Kant Sangpairoj ◽  
Nathawut Sibmooh ◽  
Christopher Power ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Electronic Cigarettes ◽  
Neuronal Cell ◽  
B Cell Lymphoma ◽  
Cyclin B1 ◽  
Time Dependent ◽  
Dependent Manner ◽  
Astrocytoma Cells ◽  
Human Astrocytes ◽  
Nickel Exposure

Abstract Nickel, a heavy metal found in electronic wastes and fume from electronic cigarettes, induces neuronal cell death and is associated with neurocognitive impairment. Astrocytes are the first line of defense against nickel after entering the brain; however, the effects of nickel on astrocytes remain unknown. Herein, we investigated the effect of nickel exposure on cell survival and proliferation and the underlying mechanisms in U-87 MG human astrocytoma cells and primary human astrocytes. Intracellular nickel levels were elevated in U-87 MG cells in both a dose- and time-dependent manner after exposure to nickel chloride. The median toxic concentrations of nickel in astrocytoma cells and primary human astrocytes were 600.60 μM and > 1,000 μM at 48 h post-exposure, respectively. Nickel exposure triggered apoptosis in concomitant with the decreased expression of anti-apoptotic B-cell lymphoma protein (Bcl-2), and increased caspase-3/7 activity. Nickel induced reactive oxygen species formation. Additionally, nickel suppressed astrocyte proliferation in a dose- and time-dependent manner by delaying G2 to M phase transition through the upregulation of cyclin B1 and p27 protein expression. These results indicate that nickel-induced cytotoxicity of astrocytes is mediated by the activation of apoptotic pathway and disruption of cell cycle regulation.

The Schizosaccharomyces pombe hus5 gene encodes a ubiquitin conjugating enzyme required for normal mitosis

1995 ◽  
Vol 108 (2) ◽  
pp. 475-486 ◽  
Author(s):  
F. al-Khodairy ◽  
T. Enoch ◽  
I.M. Hagan ◽  
A.M. Carr
Keyword(s):  
Cell Cycle ◽  
Dna Synthesis ◽  
Schizosaccharomyces Pombe ◽  
Cell Cycle Control ◽  
S Phase ◽  
Temperature Sensitive ◽  
Checkpoint Control ◽  
Ubiquitin Conjugating Enzyme ◽  
Efficient Recovery ◽  
Mediate Cell

Normal eukaryotic cells do not enter mitosis unless DNA is fully replicated and repaired. Controls called ‘checkpoints’, mediate cell cycle arrest in response to unreplicated or damaged DNA. Two independent Schizosaccharomyces pombe mutant screens, both of which aimed to isolate new elements involved in checkpoint controls, have identified alleles of the hus5+ gene that are abnormally sensitive to both inhibitors of DNA synthesis and to ionizing radiation. We have cloned and sequenced the hus5+ gene. It is a novel member of the E2 family of ubiquitin conjugating enzymes (UBCs). To understand the role of hus5+ in cell cycle control we have characterized the phenotypes of the hus5 mutants and the hus5 gene disruption. We find that, whilst the mutants are sensitive to inhibitors of DNA synthesis and to irradiation, this is not due to an inability to undergo mitotic arrest. Thus, the hus5+ gene product is not directly involved in checkpoint control. However, in common with a large class of previously characterized checkpoint genes, it is required for efficient recovery from DNA damage or S-phase arrest and manifests a rapid death phenotype in combination with a temperature sensitive S phase and late S/G2 phase cdc mutants. In addition, hus5 deletion mutants are severely impaired in growth and exhibit high levels of abortive mitoses, suggesting a role for hus5+ in chromosome segregation. We conclude that this novel UBC enzyme plays multiple roles and is virtually essential for cell proliferation.

scholarly journals Xanthohumol Induces Growth Inhibition and Apoptosis in Ca Ski Human Cervical Cancer Cells

2015 ◽  
Vol 2015 ◽  
pp. 1-10 ◽  
Author(s):  
Wai Kuan Yong ◽  
Sri Nurestri Abd Malek
Keyword(s):  
Cell Cycle ◽  
Cervical Cancer ◽  
Cancer Cells ◽  
Cancer Cell ◽  
Morphological Changes ◽  
S Phase ◽  
Phase Cell ◽  
Cervical Cancer Cell Line ◽  
Dependent Manner ◽  
Cervical Cancer Cells

We investigate induction of apoptosis by xanthohumol on Ca Ski cervical cancer cell line. Xanthohumol is a prenylated chalcone naturally found in hop plants, previously reported to be an effective anticancer agent in various cancer cell lines. The present study showed that xanthohumol was effective to inhibit proliferation of Ca Ski cells based on IC50values using sulforhodamine B (SRB) assay. Furthermore, cellular and nuclear morphological changes were observed in the cells using phase contrast microscopy and Hoechst/PI fluorescent staining. In addition, 48-hour long treatment with xanthohumol triggered externalization of phosphatidylserine, changes in mitochondrial membrane potential, and DNA fragmentation in the cells. Additionally, xanthohumol mediated S phase arrest in cell cycle analysis and increased activities of caspase-3, caspase-8, and caspase-9. On the other hand, Western blot analysis showed that the expression levels of cleaved PARP, p53, and AIF increased, while Bcl-2 and XIAP decreased in a dose-dependent manner. Taken together, these findings indicate that xanthohumol-induced cell death might involve intrinsic and extrinsic apoptotic pathways, as well as downregulation of XIAP, upregulation of p53 proteins, and S phase cell cycle arrest in Ca Ski cervical cancer cells. This work suggests that xanthohumol is a potent chemotherapeutic candidate for cervical cancer.

scholarly journals Hect E3 ubiquitin ligase Tom1 controls Dia2 degradation during the cell cycle

2012 ◽  
Vol 23 (21) ◽  
pp. 4203-4211 ◽  
Author(s):  
Dong-Hwan Kim ◽  
Deanna M. Koepp
Keyword(s):  
Cell Cycle ◽  
Protein Degradation ◽  
Ubiquitin Ligase ◽  
E3 Ubiquitin Ligase ◽  
S Phase ◽  
Temperature Sensitive ◽  
Dependent Manner ◽  
Charged Residues ◽  
Phase Progression ◽  
Positively Charged

The ubiquitin proteasome system plays a pivotal role in controlling the cell cycle. The budding yeast F-box protein Dia2 is required for genomic stability and is targeted for ubiquitin-dependent degradation in a cell cycle–dependent manner, but the identity of the ubiquitination pathway is unknown. We demonstrate that the Hect domain E3 ubiquitin ligase Tom1 is required for Dia2 protein degradation. Deletion of DIA2 partially suppresses the temperature-sensitive phenotype of tom1 mutants. Tom1 is required for Dia2 ubiquitination and degradation during G1 and G2/M phases of the cell cycle, whereas the Dia2 protein is stabilized during S phase. We find that Tom1 binding to Dia2 is enhanced in G1 and reduced in S phase, suggesting a mechanism for this proteolytic switch. Tom1 recognizes specific, positively charged residues in a Dia2 degradation/NLS domain. Loss of these residues blocks Tom1-mediated turnover of Dia2 and causes a delay in G1–to–S phase progression. Deletion of DIA2 rescues a delay in the G1–to–S phase transition in the tom1Δ mutant. Together our results suggest that Tom1 targets Dia2 for degradation during the cell cycle by recognizing positively charged residues in the Dia2 degradation/NLS domain and that Dia2 protein degradation contributes to G1–to–S phase progression.

scholarly journals Imaging the fate of histone Cse4 reveals de novo replacement in S phase and subsequent stable residence at centromeres

eLife ◽  
2014 ◽  
Vol 3 ◽  
Author(s):  
Jan Wisniewski ◽  
Bassam Hajj ◽  
Jiji Chen ◽  
Gaku Mizuguchi ◽  
Hua Xiao ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Elevated Temperatures ◽  
De Novo ◽  
Histone H3 ◽  
S Phase ◽  
Nuclear Accumulation ◽  
Histone H3 Variant ◽  
Functionally Impaired ◽  
Cell Cycle Dynamics ◽  
Cell Lethality

The budding yeast centromere contains Cse4, a specialized histone H3 variant. Fluorescence pulse-chase analysis of an internally tagged Cse4 reveals that it is replaced with newly synthesized molecules in S phase, remaining stably associated with centromeres thereafter. In contrast, C-terminally-tagged Cse4 is functionally impaired, showing slow cell growth, cell lethality at elevated temperatures, and extra-centromeric nuclear accumulation. Recent studies using such strains gave conflicting findings regarding the centromeric abundance and cell cycle dynamics of Cse4. Our findings indicate that internally tagged Cse4 is a better reporter of the biology of this histone variant. Furthermore, the size of centromeric Cse4 clusters was precisely mapped with a new 3D-PALM method, revealing substantial compaction during anaphase. Cse4-specific chaperone Scm3 displays steady-state, stoichiometric co-localization with Cse4 at centromeres throughout the cell cycle, while undergoing exchange with a nuclear pool. These findings suggest that a stable Cse4 nucleosome is maintained by dynamic chaperone-in-residence Scm3.

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