One of the most prominent features of a eukaryotic cell is the nucleus, which is a complex and highly dynamic organelle. The nucleus was the first cell compartment to be discovered in 1833 by Robert Brown and is the largest organelle in the human cell. Inside the nuclear membrane is the nucleoplasm, which main function is to store DNA and enanble DNA-dependent processes such as transcription to occur in a controlled environment. The nucleoplasm contains several non-membrane bound substructures, such as nuclear bodies and nuclear speckles. Example images of proteins that localized to the nucleus can be seen in Figure 1.
In the subcellular section, 6773 genes (34% of all human protein-coding genes) have been shown to encode proteins that localize to the nucleoplasm and its sub-compartments (Figure 2). A Gene Ontology (GO)-based functional enrichment analysis of genes encoding nuclear shows an enrichment of gene associated with biological processes related to DNA repair, transcription, RNA processing, chromatin modification, regulation of gene expression, differentiation and development. Approximately 67% (n=4556) of the proteins that localize to the nucleoplasm can also be detected in additional cellular compartments, with 8% (n=563) only being detected in the other major nuclear compartments; nucleoli and nuclear membrane. The most common additional localizations except for the nucleoli are the cytosol and vesicles.
Figure 1. Examples of proteins localized to the nucleoplasm and its substructures. PDS5A is thought to keep the sister chromatids in place during mitosis and also play a role in DNA repair. PDS5A has been localized to the nucleoplasm (detected in A-431 cells). TP53BP1 is involved in DNA damage response and is localized to nuclear bodies (detected in A-431 cells). SRRM2 is known to be involved in pre-mRNA splicing and is localized to nuclear speckles (detected in A-431 cells).
34% (6773 proteins) of all human proteins have been experimentally detected in the nucleoplasm by the Human Protein Atlas.
2844 proteins in the nucleoplasm are supported by experimental evidence and out of these 766 proteins are enhanced by the Human Protein Atlas.
4556 proteins in the nucleoplasm have multiple locations.
1338 proteins in the nucleoplasm show single cell variation.
Proteins localizing to the nucleoplasm are mainly involved in RNA processing, transcription, chromatin modification and DNA repair, differentiation and development.
Figure 2. 34% of all human protein-coding genes encode proteins that have been shown to localize to the nucleoplasm. Each bar is clickable and gives a search result of proteins that belong to the selected category.
The nucleus of human cells varies in size depending on cell type and cell cycle stage, but is usually around 10 μm in diameter. The nucleus mainly contains DNA and proteins interacting with DNA in a complex called chromatin. At the first level of chromatin organization, the DNA is wrapped around proteins known as histones, which provides both a way of compacting the long DNA molecules as well as a mechanism to regulate DNA-dependent cellular processes. The chromatin is then further compacted and organized in intricate ways, while yet remaining dynamic. The most densely condensed chromatin, known as heterochromatin, is usually organized in the nuclear periphery while the less packed euchromatin is dispersed throughout the whole nucleus (Spector DL. (1993)).
Many of the nuclear proteins are localized to the entire nucleoplasm where they give rise to a smooth or punctate staining pattern. However, the nucleoplasm is far from homogeneous. It contains several non-membrane bound sub compartments, collectively called nuclear bodies, acting as self-organizing clusters for different nuclear activities. Except for the nucleolus, the most prominent subcompartments are nuclear speckles and nuclear bodies (Lamond AI et al. (1998)). Nuclear speckles, in the form of splicing speckles and paraspeckles, are formed in interchromatin granule clusters (IGCs) and contain pre-messenger RNA (pre-mRNA) splicing factors such as small nuclear ribonucleoprotein particles (snRNPs) (SWIFT H. (1959); Lamond AI et al. (2003)). These granules are connected by fine fibrils, forming clusters that can be seen directly by electron microscopy (Thiry M. (1995)). The appearance of nuclear speckles varies between cell lines, but they all share an irregular mottled pattern, which may change in both size and shape over time. Nuclear bodies vary in size, number and location dependent on the type of nuclear body and the cell line. Cajal bodies (CBs) and gemini of Cajal bodies (gems) are usually found in close proximity to each other, but CBs mainly contain the protein Coilin and snRNPs, while gems mainly contain the snRNP-interacting complex survival of motor neuron (SMN) (Sleeman JE et al. (1999); Darzacq X et al. (2002); Jády BE et al. (2003); Liu Q et al. (1996); Lefebvre S et al. (1995); Fischer U et al. (1997)). PML bodies are characterized by the presence of the PML protein, which acts as a hub for assembly of a macromolecular complex that is highly dynamic and can contain a variety of different proteins (Lallemand-Breitenbach V et al. (2010)). As CBs, gems, PML bodies and other nuclear bodies are all seen as distinct spots scattered throughout the nucleoplasm, they are difficult to differentiate without the use of co-localizing protein markers.
In the subcellular section, there are also annotations of proteins that localize to kinetochores or the perichromosomal layer during mitosis. Kinetochores are large protein structures that assemble on centromeric chromatin and act as an attachment site for microtubules of the mitotic spindle. While the inner kinetochore persists through the cell cycle, the outer kinetochore is assembled only during cell division. Components of the kinetochore include structural proteins, motor proteins and regulatory checkpoint proteins. Upon entry into mitosis, there are also certain proteins and RNP complexes that localize specifically to the surface of the condensed mitotic chromosomes, known as the perichromosomal layer (Booth DG et al. (2017); Stenström L et al. (2020); Ljungberg O et al. (1983)). Many of these proteins, including MKI67 that is considered a major organizer of this region, also localize to nucleoli, and in particular the rim of nucleoli, in interphase.
A selection of proteins localized to the nucleus, nuclear speckles and nuclear bodies suitable as markers can be found in Table 1. Highly expressed nuclear proteins are summarized in Table 2. Images showing the different nuclear substructures can be seen in Figure 3.
Table 1. Selection of proteins suitable as markers for the nucleus or its substructures.
Figure 3. Examples showing the different nuclear substructures and staining patterns. LSM2 is a protein that might be involved in pre-mRNA splicing and shows a nucleoplasmic punctate staining pattern (detected in SK-MEL-30 cells). CTBP1 is a co-repressor targeting various transcription factors and shows a smooth nucleoplasmic staining pattern (detected in A-431 cells). NOSIP is an E3 ubiquitin-protein regulating several catalytic processes and is localized to the nucleus (detected in U2OS cells). RBM25 is involved in pre-mRNA splicing activities and has been shown to localize to nuclear speckles (detected in HaCaT cells). NPAT is a known Cajal body protein and is required for proper G1/S transition. In the Subcellular Section, NPAT localizes to nuclear bodies (detected in CACO-2 cells). DAXX is a transcription co-repressor involved in a number of different nuclear activities and is known to localize to several nuclear substructures such as PML bodies and centromeres. In the Subcellular Section, DAXX localizes to nuclear bodies (detected in A-431 cells).
Figure 4. 3D-view of the nucleoplasm in U2OS, visualized by immunofluorescent staining of HNRNPC. The morphology of nuclei in human induced stem cells can be seen in the Allen Cell Explorer.
The function of the nucleoplasm
The main function of the nucleus is to store and condense the majority of the human genome, but a major function for proteins that localize to the nucleoplasm is also to participate in and regulate DNA-dependent functions and cellular processes, such as transcription, RNA splicing, RNP assembly, DNA repair, and replication.
Despite the fact that the nuclear substructures are not membrane bound, highly specific tasks are carried out in these regions.
Splicing speckles are enriched for pre-mRNA splicing factors (Lamond AI et al. (2003); Melcák I et al. (2000)), and are thought to act as a regulatory site for transcription and pre-mRNA processing, with transcription occurring in close proximity (Spector DL et al. (1991); Misteli T et al. (1997); Cmarko D et al. (1999)). Paraspeckles can sequester nuclear proteins and RNA, thus providing a means for regulation of gene expression. Both splicing speckles and paraspeckles have highly dynamic compositions. CBs probably function as a modification site of snRNPs into fully functional splicing factors before they enter other parts of the cell (Sleeman JE et al. (1999); Darzacq X et al. (2002); Jády BE et al. (2003)). The closely related gems play an important role in the synthesis of cytoplasmic snRNP (Liu Q et al. (1996); Lefebvre S et al. (1995); Fischer U et al. (1997)). As previously mentioned, gems contain the SMN1 protein which has been found to be responsible for the onset of spinal muscular atrophy (SMA). SMA is one of the most lethal autosomal recessive disorders and genetic defects in the SMN gene could cause progressive muscular and mobility impairments (Lefebvre S et al. (1995)). PML bodies have been found to be highly diverse and have been suggested to perform an ever-growing number of tasks in the cell, ranging from apoptosis regulation to anti-viral protection, and much about the function remains to be unraveled (Lallemand-Breitenbach V et al. (2010)).
Kinetochores have an essential role in ensuring proper segregation of sister chromatids in mitosis and meiosis. Apart from serving as a physical attachment point for spindle microtubules, kinetochores contain a number of motor proteins and regulatory factors that orchestrate and control the movements of chromosomes during cell division.The function of the peripheral layer of mitotic chromosomes is not fully known, but it has been suggested to be involved in mitotic chromosome structure, to act as a physical barrier protecting mitotic chromatin from cytoplasmic proteins following nuclear envelope breakdown, and to keep mitotic chromosomes from sticking to one another (Van Hooser AA et al. (2005)). In agreement, MKI67 is essential for proper chromosome segregation and has been shown to act as an emulsifying shield around the chromosomes during mitosis (Booth DG et al. (2014); Cuylen S et al. (2016)). In addition, the peripheral layer may act as a landing pad, concentrating nucleolar proteins to aid in nucleolar reactivation during mitotic exit, and helping to ensure equal distribution of its components to daughter cells.
Gene Ontology (GO) analysis of genes encoding proteins mainly localized to the nucleus shows functions that are well in-line with known functions for this compartment. The enriched terms for the GO domain Biological Process are mainly related to transcription and DNA repair (Figure 5a). Enrichment analysis of the GO domain Molecular Function, gives enrichment of terms related to DNA binding, RNA binding, chromatin binding, and regulation of transcription as well as replication (Figure 5b).
Figure 5a Gene Ontology-based enrichment analysis for the nucleoplasm proteome showing the significantly enriched terms for the GO domain Biological Process. Each bar is clickable and gives a search result of proteins that belong to the selected category.
Figure 5b Gene Ontology-based enrichment analysis for the nucleoplasm proteome showing the significantly enriched terms for the GO domain Molecular Function. Each bar is clickable and gives a search result of proteins that belong to the selected category.
Nucleoplasmic proteins with multiple locations
In the subcellular section, approximately 67% (n=4556) of the proteins that localize to the nucleoplasm also localize to other cell compartments (Figure 6). 563 of the proteins in the nucleoplasm (8%) only localize to other nuclear structures. The network plot shows that the most common locations shared with the nucleus are the cytosol, nucleoli and vesicles. Given that the nucleus is involved both in import and export of proteins to the cytoplasm and other compartments of the cell, these dual locations could highlight proteins functioning in nuclear trafficking as well as proteins functioning in various signaling cascades. Multilocalization between the nucleus and a number of cellular compartments, including nucleoli and the cytosol, are significantly overrepresented, while proteins localizing to the nucleus and to the plasma membrane are significantly underrepresented. Examples of multilocalizing proteins within the nucleoplasmic proteome can be seen in Figure 7.
Figure 6. Interactive network plot of nuclear proteins with multiple localizations. The numbers in the connecting nodes show the proteins that are localized to the nucleus and to one or more additional locations. Only connecting nodes containing more than one protein and at least 0.7% of proteins in the nuclear proteome are shown. The circle sizes are related to the number of proteins. The cyan colored nodes show combinations that are significantly overrepresented, while magenta colored nodes show combinations that are significantly underrepresented as compared to the probability of observing that combination based on the frequency of each annotation and a hypergeometric test (p≤0.05). Note that this calculation is only done for proteins with dual localizations. Each node is clickable and results in a list of all proteins that are found in the connected organelles.
Figure 7. Examples of multilocalizing proteins in the nuclear proteome. The examples show common or overrepresented combinations for multilocalizing proteins in the nuclear proteome. IPO7 is functioning in the nuclear import of proteins and is known to be located at both the nucleoplasmic and cytoplasmic side of the nuclear pore complex (detected in A-431 cells). RRAGC is shuttling between the nucleus and the cytoplasm. It plays a crucial role in the initiation of the TOR signaling cascade where it is required for the amino acid induced relocalization of mTORC1 into the lysosomes (detected in U2OS cells). SENP3 is located in both the nucleoli and the nucleoplasm known to interact with sumoylated proteins regulating the transcriptional capacity in the cell and is also required for rRNA processing (detected in MCF7 cells).
Expression levels of nucleoplasm proteins in tissue
Transcriptome analysis and classification of genes into tissue distribution categories (Figure 8) shows that a larger portion of the genes encoding proteins localizing to the nucleoplasm and its substructures are detected in all tissues, compared to all genes presented in the subcellular section. Significantly smaller portions of these genes are detected in many or in some tissues. Thus, the nucleoplasm is a structure that contains a larger portion of ubiquitously expressed proteins.
Figure 8. Bar plot showing the percentage of genes in different tissue distribution categories for nuclear protein-coding genes compared to all genes in the subcellular section. Asterisk marks a statistically significant deviation (p≤0.05) in the number of genes in a category based on a binomial statistical test. Each bar is clickable and gives a search result of proteins that belong to the selected category.
Stadler C et al., Systematic validation of antibody binding and protein subcellular localization using siRNA and confocal microscopy.J Proteomics. (2012)
PubMed: 22361696 DOI: 10.1016/j.jprot.2012.01.030
Poser I et al., BAC TransgeneOmics: a high-throughput method for exploration of protein function in mammals.Nat Methods. (2008)
PubMed: 18391959 DOI: 10.1038/nmeth.1199
Hildreth AD et al., Single-cell sequencing of human white adipose tissue identifies new cell states in health and obesity.Nat Immunol. (2021)
PubMed: 33907320 DOI: 10.1038/s41590-021-00922-4
He S et al., Single-cell transcriptome profiling of an adult human cell atlas of 15 major organs.Genome Biol. (2020)
PubMed: 33287869 DOI: 10.1186/s13059-020-02210-0
Bhat-Nakshatri P et al., A single-cell atlas of the healthy breast tissues reveals clinically relevant clusters of breast epithelial cells.Cell Rep Med. (2021)
PubMed: 33763657 DOI: 10.1016/j.xcrm.2021.100219
Lukassen S et al., SARS-CoV-2 receptor ACE2 and TMPRSS2 are primarily expressed in bronchial transient secretory cells.EMBO J. (2020)
PubMed: 32246845 DOI: 10.15252/embj.20105114
Wang W et al., Single-cell transcriptomic atlas of the human endometrium during the menstrual cycle.Nat Med. (2020)
PubMed: 32929266 DOI: 10.1038/s41591-020-1040-z
Menon M et al., Single-cell transcriptomic atlas of the human retina identifies cell types associated with age-related macular degeneration.Nat Commun. (2019)
PubMed: 31653841 DOI: 10.1038/s41467-019-12780-8
Ulrich ND et al., Cellular heterogeneity of human fallopian tubes in normal and hydrosalpinx disease states identified using scRNA-seq.Dev Cell. (2022)
PubMed: 35320732 DOI: 10.1016/j.devcel.2022.02.017
Wang L et al., Single-cell reconstruction of the adult human heart during heart failure and recovery reveals the cellular landscape underlying cardiac function.Nat Cell Biol. (2020)
PubMed: 31915373 DOI: 10.1038/s41556-019-0446-7
MacParland SA et al., Single cell RNA sequencing of human liver reveals distinct intrahepatic macrophage populations.Nat Commun. (2018)
PubMed: 30348985 DOI: 10.1038/s41467-018-06318-7
Tabula Sapiens Consortium* et al., The Tabula Sapiens: A multiple-organ, single-cell transcriptomic atlas of humans.Science. (2022)
PubMed: 35549404 DOI: 10.1126/science.abl4896
Wagner M et al., Single-cell analysis of human ovarian cortex identifies distinct cell populations but no oogonial stem cells.Nat Commun. (2020)
PubMed: 32123174 DOI: 10.1038/s41467-020-14936-3
Qadir MMF et al., Single-cell resolution analysis of the human pancreatic ductal progenitor cell niche.Proc Natl Acad Sci U S A. (2020)
PubMed: 32354994 DOI: 10.1073/pnas.1918314117
Vento-Tormo R et al., Single-cell reconstruction of the early maternal-fetal interface in humans.Nature. (2018)
PubMed: 30429548 DOI: 10.1038/s41586-018-0698-6
Wang Y et al., Single-cell transcriptome analysis reveals differential nutrient absorption functions in human intestine.J Exp Med. (2020)
PubMed: 31753849 DOI: 10.1084/jem.20191130
De Micheli AJ et al., A reference single-cell transcriptomic atlas of human skeletal muscle tissue reveals bifurcated muscle stem cell populations.Skelet Muscle. (2020)
PubMed: 32624006 DOI: 10.1186/s13395-020-00236-3
Solé-Boldo L et al., Single-cell transcriptomes of the human skin reveal age-related loss of fibroblast priming.Commun Biol. (2020)
PubMed: 32327715 DOI: 10.1038/s42003-020-0922-4
Gilvesy A et al., Spatiotemporal characterization of cellular tau pathology in the human locus coeruleus-pericoerulear complex by three-dimensional imaging.Acta Neuropathol. (2022)
PubMed: 36040521 DOI: 10.1007/s00401-022-02477-6
Jin H et al., Systematic transcriptional analysis of human cell lines for gene expression landscape and tumor representation.Nat Commun. (2023)
PubMed: 37669926 DOI: 10.1038/s41467-023-41132-w
Schubert M et al., Perturbation-response genes reveal signaling footprints in cancer gene expression.Nat Commun. (2018)
PubMed: 29295995 DOI: 10.1038/s41467-017-02391-6
Jiang P et al., Systematic investigation of cytokine signaling activity at the tissue and single-cell levels.Nat Methods. (2021)
PubMed: 34594031 DOI: 10.1038/s41592-021-01274-5
Jin L et al., Targeting of CD44 eradicates human acute myeloid leukemic stem cells.Nat Med. (2006)
PubMed: 16998484 DOI: 10.1038/nm1483
Magis AT et al., Untargeted longitudinal analysis of a wellness cohort identifies markers of metastatic cancer years prior to diagnosis.Sci Rep. (2020)
PubMed: 33004987 DOI: 10.1038/s41598-020-73451-z
Santarius T et al., GLO1-A novel amplified gene in human cancer.Genes Chromosomes Cancer. (2010)
PubMed: 20544845 DOI: 10.1002/gcc.20784
Berggrund M et al., Identification of Candidate Plasma Protein Biomarkers for Cervical Cancer Using the Multiplex Proximity Extension Assay.Mol Cell Proteomics. (2019)
PubMed: 30692274 DOI: 10.1074/mcp.RA118.001208
Virgilio L et al., Deregulated expression of TCL1 causes T cell leukemia in mice.Proc Natl Acad Sci U S A. (1998)
PubMed: 9520462 DOI: 10.1073/pnas.95.7.3885
Saberi Hosnijeh F et al., Proteomic markers with prognostic impact on outcome of chronic lymphocytic leukemia patients under chemo-immunotherapy: results from the HOVON 109 study.Exp Hematol. (2020)
PubMed: 32781097 DOI: 10.1016/j.exphem.2020.08.002
Satelli A et al., Galectin-4 functions as a tumor suppressor of human colorectal cancer.Int J Cancer. (2011)
PubMed: 21064109 DOI: 10.1002/ijc.25750
Harlid S et al., A two-tiered targeted proteomics approach to identify pre-diagnostic biomarkers of colorectal cancer risk.Sci Rep. (2021)
PubMed: 33664295 DOI: 10.1038/s41598-021-83968-6
Sun X et al., Prospective Proteomic Study Identifies Potential Circulating Protein Biomarkers for Colorectal Cancer Risk.Cancers (Basel). (2022)
PubMed: 35805033 DOI: 10.3390/cancers14133261
Bhardwaj M et al., Comparison of Proteomic Technologies for Blood-Based Detection of Colorectal Cancer.Int J Mol Sci. (2021)
PubMed: 33530402 DOI: 10.3390/ijms22031189
Chen H et al., Head-to-Head Comparison and Evaluation of 92 Plasma Protein Biomarkers for Early Detection of Colorectal Cancer in a True Screening Setting.Clin Cancer Res. (2015)
PubMed: 26015516 DOI: 10.1158/1078-0432.CCR-14-3051
Thorsen SB et al., Detection of serological biomarkers by proximity extension assay for detection of colorectal neoplasias in symptomatic individuals.J Transl Med. (2013)
PubMed: 24107468 DOI: 10.1186/1479-5876-11-253
Mahboob S et al., A novel multiplexed immunoassay identifies CEA, IL-8 and prolactin as prospective markers for Dukes' stages A-D colorectal cancers.Clin Proteomics. (2015)
PubMed: 25987887 DOI: 10.1186/s12014-015-9081-x
He W et al., Attenuation of TNFSF10/TRAIL-induced apoptosis by an autophagic survival pathway involving TRAF2- and RIPK1/RIP1-mediated MAPK8/JNK activation.Autophagy. (2012)
PubMed: 23051914 DOI: 10.4161/auto.22145
Enroth S et al., A two-step strategy for identification of plasma protein biomarkers for endometrial and ovarian cancer.Clin Proteomics. (2018)
PubMed: 30519148 DOI: 10.1186/s12014-018-9216-y
Jung CS et al., Serum GFAP is a diagnostic marker for glioblastoma multiforme.Brain. (2007)
PubMed: 17998256 DOI: 10.1093/brain/awm263
Jaworski DM et al., BEHAB (brain enriched hyaluronan binding) is expressed in surgical samples of glioma and in intracranial grafts of invasive glioma cell lines.Cancer Res. (1996)
Zhang X et al., CEACAM5 stimulates the progression of non-small-cell lung cancer by promoting cell proliferation and migration.J Int Med Res. (2020)
PubMed: 32993395 DOI: 10.1177/0300060520959478
Xu F et al., A Linear Discriminant Analysis Model Based on the Changes of 7 Proteins in Plasma Predicts Response to Anlotinib Therapy in Advanced Non-Small Cell Lung Cancer Patients.Front Oncol. (2021)
PubMed: 35070967 DOI: 10.3389/fonc.2021.756902
Dagnino S et al., Prospective Identification of Elevated Circulating CDCP1 in Patients Years before Onset of Lung Cancer.Cancer Res. (2021)
PubMed: 33574093 DOI: 10.1158/0008-5472.CAN-20-3454
Álvez MB et al., Next generation pan-cancer blood proteome profiling using proximity extension assay.Nat Commun. (2023)
PubMed: 37463882 DOI: 10.1038/s41467-023-39765-y
Wik L et al., Proximity Extension Assay in Combination with Next-Generation Sequencing for High-throughput Proteome-wide Analysis.Mol Cell Proteomics. (2021)
PubMed: 34715355 DOI: 10.1016/j.mcpro.2021.100168
Zeiler M et al., A Protein Epitope Signature Tag (PrEST) library allows SILAC-based absolute quantification and multiplexed determination of protein copy numbers in cell lines.Mol Cell Proteomics. (2012)
PubMed: 21964433 DOI: 10.1074/mcp.O111.009613
Peng Y et al., Identification of key biomarkers associated with cell adhesion in multiple myeloma by integrated bioinformatics analysis.Cancer Cell Int. (2020)
PubMed: 32581652 DOI: 10.1186/s12935-020-01355-z
Gyllensten U et al., Next Generation Plasma Proteomics Identifies High-Precision Biomarker Candidates for Ovarian Cancer.Cancers (Basel). (2022)
PubMed: 35406529 DOI: 10.3390/cancers14071757
Enroth S et al., High throughput proteomics identifies a high-accuracy 11 plasma protein biomarker signature for ovarian cancer.Commun Biol. (2019)
PubMed: 31240259 DOI: 10.1038/s42003-019-0464-9
Wang Z et al., DNER promotes epithelial-mesenchymal transition and prevents chemosensitivity through the Wnt/β-catenin pathway in breast cancer.Cell Death Dis. (2020)
PubMed: 32811806 DOI: 10.1038/s41419-020-02903-1
Liu S et al., Discovery of CASP8 as a potential biomarker for high-risk prostate cancer through a high-multiplex immunoassay.Sci Rep. (2021)
PubMed: 33828176 DOI: 10.1038/s41598-021-87155-5
Orchard S et al., The MIntAct project--IntAct as a common curation platform for 11 molecular interaction databases.Nucleic Acids Res. (2014)
PubMed: 24234451 DOI: 10.1093/nar/gkt1115
Varadi M et al., AlphaFold Protein Structure Database: massively expanding the structural coverage of protein-sequence space with high-accuracy models.Nucleic Acids Res. (2022)
PubMed: 34791371 DOI: 10.1093/nar/gkab1061
Bird RP., Observation and quantification of aberrant crypts in the murine colon treated with a colon carcinogen: preliminary findings.Cancer Lett. (1987)
PubMed: 3677050 DOI: 10.1016/0304-3835(87)90157-1
HUXLEY AF et al., Structural changes in muscle during contraction; interference microscopy of living muscle fibres.Nature. (1954)
HUXLEY H et al., Changes in the cross-striations of muscle during contraction and stretch and their structural interpretation.Nature. (1954)
Cho RJ et al., Transcriptional regulation and function during the human cell cycle.Nat Genet. (2001)
PubMed: 11137997 DOI: 10.1038/83751
Whitfield ML et al., Identification of genes periodically expressed in the human cell cycle and their expression in tumors.Mol Biol Cell. (2002)
PubMed: 12058064 DOI: 10.1091/mbc.02-02-0030.
Boström J et al., Comparative cell cycle transcriptomics reveals synchronization of developmental transcription factor networks in cancer cells.PLoS One. (2017)
PubMed: 29228002 DOI: 10.1371/journal.pone.0188772
Lane KR et al., Cell cycle-regulated protein abundance changes in synchronously proliferating HeLa cells include regulation of pre-mRNA splicing proteins.PLoS One. (2013)
PubMed: 23520512 DOI: 10.1371/journal.pone.0058456
Ohta S et al., The protein composition of mitotic chromosomes determined using multiclassifier combinatorial proteomics.Cell. (2010)
PubMed: 20813266 DOI: 10.1016/j.cell.2010.07.047
Ly T et al., A proteomic chronology of gene expression through the cell cycle in human myeloid leukemia cells.Elife. (2014)
PubMed: 24596151 DOI: 10.7554/eLife.01630
Pagliuca FW et al., Quantitative proteomics reveals the basis for the biochemical specificity of the cell-cycle machinery.Mol Cell. (2011)
PubMed: 21816347 DOI: 10.1016/j.molcel.2011.05.031
Ly T et al., Proteomic analysis of the response to cell cycle arrests in human myeloid leukemia cells.Elife. (2015)
PubMed: 25555159 DOI: 10.7554/eLife.04534
Dueck H et al., Variation is function: Are single cell differences functionally important?: Testing the hypothesis that single cell variation is required for aggregate function.Bioessays. (2016)
PubMed: 26625861 DOI: 10.1002/bies.201500124
Snijder B et al., Origins of regulated cell-to-cell variability.Nat Rev Mol Cell Biol. (2011)
PubMed: 21224886 DOI: 10.1038/nrm3044
Cooper S et al., Membrane-elution analysis of content of cyclins A, B1, and E during the unperturbed mammalian cell cycle.Cell Div. (2007)
PubMed: 17892542 DOI: 10.1186/1747-1028-2-28
Davis PK et al., Biological methods for cell-cycle synchronization of mammalian cells.Biotechniques. (2001)
PubMed: 11414226 DOI: 10.2144/01306rv01
Scialdone A et al., Computational assignment of cell-cycle stage from single-cell transcriptome data.Methods. (2015)
PubMed: 26142758 DOI: 10.1016/j.ymeth.2015.06.021
Sakaue-Sawano A et al., Visualizing spatiotemporal dynamics of multicellular cell-cycle progression.Cell. (2008)
PubMed: 18267078 DOI: 10.1016/j.cell.2007.12.033
Grant GD et al., Identification of cell cycle-regulated genes periodically expressed in U2OS cells and their regulation by FOXM1 and E2F transcription factors.Mol Biol Cell. (2013)
PubMed: 24109597 DOI: 10.1091/mbc.E13-05-0264
Semple JW et al., An essential role for Orc6 in DNA replication through maintenance of pre-replicative complexes.EMBO J. (2006)
PubMed: 17053779 DOI: 10.1038/sj.emboj.7601391
Janmey PA et al., Viscoelastic properties of vimentin compared with other filamentous biopolymer networks.J Cell Biol. (1991)
Köster S et al., Intermediate filament mechanics in vitro and in the cell: from coiled coils to filaments, fibers and networks.Curr Opin Cell Biol. (2015)
PubMed: 25621895 DOI: 10.1016/j.ceb.2015.01.001
Herrmann H et al., Intermediate filaments: from cell architecture to nanomechanics.Nat Rev Mol Cell Biol. (2007)
PubMed: 17551517 DOI: 10.1038/nrm2197
Schaefer AM et al., The epidemiology of mitochondrial disorders--past, present and future.Biochim Biophys Acta. (2004)
PubMed: 15576042 DOI: 10.1016/j.bbabio.2004.09.005
Lange A et al., Classical nuclear localization signals: definition, function, and interaction with importin alpha.J Biol Chem. (2007)
PubMed: 17170104 DOI: 10.1074/jbc.R600026200
Ashmarina LI et al., 3-Hydroxy-3-methylglutaryl coenzyme A lyase: targeting and processing in peroxisomes and mitochondria.J Lipid Res. (1999)
Wang SC et al., Nuclear translocation of the epidermal growth factor receptor family membrane tyrosine kinase receptors.Clin Cancer Res. (2009)
PubMed: 19861462 DOI: 10.1158/1078-0432.CCR-08-2813
Pancholi V., Multifunctional alpha-enolase: its role in diseases.Cell Mol Life Sci. (2001)
PubMed: 11497239 DOI: 10.1007/pl00000910
Chapple CE et al., Extreme multifunctional proteins identified from a human protein interaction network.Nat Commun. (2015)
PubMed: 26054620 DOI: 10.1038/ncomms8412
Dechat T et al., Nuclear lamins: major factors in the structural organization and function of the nucleus and chromatin.Genes Dev. (2008)
PubMed: 18381888 DOI: 10.1101/gad.1652708
Gruenbaum Y et al., The nuclear lamina comes of age.Nat Rev Mol Cell Biol. (2005)
PubMed: 15688064 DOI: 10.1038/nrm1550
Stuurman N et al., Nuclear lamins: their structure, assembly, and interactions.J Struct Biol. (1998)
PubMed: 9724605 DOI: 10.1006/jsbi.1998.3987
Paine PL et al., Nuclear envelope permeability.Nature. (1975)
Reichelt R et al., Correlation between structure and mass distribution of the nuclear pore complex and of distinct pore complex components.J Cell Biol. (1990)
CALLAN HG et al., Experimental studies on amphibian oocyte nuclei. I. Investigation of the structure of the nuclear membrane by means of the electron microscope.Proc R Soc Lond B Biol Sci. (1950)
WATSON ML., The nuclear envelope; its structure and relation to cytoplasmic membranes.J Biophys Biochem Cytol. (1955)
BAHR GF et al., The fine structure of the nuclear membrane in the larval salivary gland and midgut of Chironomus.Exp Cell Res. (1954)
Terasaki M et al., A new model for nuclear envelope breakdown.Mol Biol Cell. (2001)
Dultz E et al., Systematic kinetic analysis of mitotic dis- and reassembly of the nuclear pore in living cells.J Cell Biol. (2008)
PubMed: 18316408 DOI: 10.1083/jcb.200707026
Salina D et al., Cytoplasmic dynein as a facilitator of nuclear envelope breakdown.Cell. (2002)
Beaudouin J et al., Nuclear envelope breakdown proceeds by microtubule-induced tearing of the lamina.Cell. (2002)
Gerace L et al., The nuclear envelope lamina is reversibly depolymerized during mitosis.Cell. (1980)
Ellenberg J et al., Nuclear membrane dynamics and reassembly in living cells: targeting of an inner nuclear membrane protein in interphase and mitosis.J Cell Biol. (1997)
Yang L et al., Integral membrane proteins of the nuclear envelope are dispersed throughout the endoplasmic reticulum during mitosis.J Cell Biol. (1997)
Bione S et al., Identification of a novel X-linked gene responsible for Emery-Dreifuss muscular dystrophy.Nat Genet. (1994)
PubMed: 7894480 DOI: 10.1038/ng1294-323
Boisvert FM et al., The multifunctional nucleolus.Nat Rev Mol Cell Biol. (2007)
PubMed: 17519961 DOI: 10.1038/nrm2184
Cuylen S et al., Ki-67 acts as a biological surfactant to disperse mitotic chromosomes.Nature. (2016)
PubMed: 27362226 DOI: 10.1038/nature18610
Stenström L et al., Mapping the nucleolar proteome reveals a spatiotemporal organization related to intrinsic protein disorder.Mol Syst Biol. (2020)
PubMed: 32744794 DOI: 10.15252/msb.20209469
Visintin R et al., The nucleolus: the magician's hat for cell cycle tricks.Curr Opin Cell Biol. (2000)
Marciniak RA et al., Nucleolar localization of the Werner syndrome protein in human cells.Proc Natl Acad Sci U S A. (1998)
Tamanini F et al., The fragile X-related proteins FXR1P and FXR2P contain a functional nucleolar-targeting signal equivalent to the HIV-1 regulatory proteins.Hum Mol Genet. (2000)
Willemsen R et al., Association of FMRP with ribosomal precursor particles in the nucleolus.Biochem Biophys Res Commun. (1996)
PubMed: 8769090 DOI: 10.1006/bbrc.1996.1126
Isaac C et al., Characterization of the nucleolar gene product, treacle, in Treacher Collins syndrome.Mol Biol Cell. (2000)
Lamond AI et al., Structure and function in the nucleus.Science. (1998)
SWIFT H., Studies on nuclear fine structure.Brookhaven Symp Biol. (1959)
Lamond AI et al., Nuclear speckles: a model for nuclear organelles.Nat Rev Mol Cell Biol. (2003)
PubMed: 12923522 DOI: 10.1038/nrm1172
Thiry M., The interchromatin granules.Histol Histopathol. (1995)
Sleeman JE et al., Newly assembled snRNPs associate with coiled bodies before speckles, suggesting a nuclear snRNP maturation pathway.Curr Biol. (1999)
Darzacq X et al., Cajal body-specific small nuclear RNAs: a novel class of 2'-O-methylation and pseudouridylation guide RNAs.EMBO J. (2002)
PubMed: 12032087 DOI: 10.1093/emboj/21.11.2746
Jády BE et al., Modification of Sm small nuclear RNAs occurs in the nucleoplasmic Cajal body following import from the cytoplasm.EMBO J. (2003)
PubMed: 12682020 DOI: 10.1093/emboj/cdg187
Liu Q et al., A novel nuclear structure containing the survival of motor neurons protein.EMBO J. (1996)
Lefebvre S et al., Identification and characterization of a spinal muscular atrophy-determining gene.Cell. (1995)
Fischer U et al., The SMN-SIP1 complex has an essential role in spliceosomal snRNP biogenesis.Cell. (1997)