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1.
Nat Commun ; 15(1): 3880, 2024 May 08.
Article En | MEDLINE | ID: mdl-38719804

Correlative evidence has suggested that the methyl-CpG-binding protein MeCP2 contributes to the formation of heterochromatin condensates via liquid-liquid phase separation. This interpretation has been reinforced by the observation that heterochromatin, DNA methylation and MeCP2 co-localise within prominent foci in mouse cells. The findings presented here revise this view. MeCP2 localisation is independent of heterochromatin as MeCP2 foci persist even when heterochromatin organisation is disrupted. Additionally, MeCP2 foci fail to show hallmarks of phase separation in live cells. Importantly, we find that mouse cellular models are highly atypical as MeCP2 distribution is diffuse in most mammalian species, including humans. Notably, MeCP2 foci are absent in Mus spretus which is a mouse subspecies lacking methylated satellite DNA repeats. We conclude that MeCP2 has no intrinsic tendency to form condensates and its localisation is independent of heterochromatin. Instead, the distribution of MeCP2 in the nucleus is primarily determined by global DNA methylation patterns.


DNA Methylation , Heterochromatin , Methyl-CpG-Binding Protein 2 , Methyl-CpG-Binding Protein 2/metabolism , Methyl-CpG-Binding Protein 2/genetics , Heterochromatin/metabolism , Animals , Mice , Humans , Cell Nucleus/metabolism , Protein Binding , DNA/metabolism , DNA, Satellite/metabolism , DNA, Satellite/genetics , Phase Separation
2.
Int J Biol Sci ; 20(7): 2748-2762, 2024.
Article En | MEDLINE | ID: mdl-38725859

Abnormal nuclear enlargement is a diagnostic and physical hallmark of malignant tumors. Large nuclei are positively associated with an increased risk of developing metastasis; however, a large nucleus is inevitably more resistant to cell migration due to its size. The present study demonstrated that the nuclear size of primary colorectal cancer (CRC) cells at an advanced stage was larger than cells at an early stage. In addition, the nuclei of CRC liver metastases were larger than those of the corresponding primary CRC tissues. CRC cells were sorted into large-nucleated cells (LNCs) and small-nucleated cells (SNCs). Purified LNCs exhibited greater constricted migratory and metastatic capacity than SNCs in vitro and in vivo. Mechanistically, ErbB4 was highly expressed in LNCs, which phosphorylated lamin A/C at serine 22 via the ErbB4-Akt1 signaling pathway. Furthermore, the level of phosphorylated lamin A/C was a negative determinant of nuclear stiffness. Taken together, CRC LNCs possessed greater constricted migratory and metastatic potential than SNCs due to ErbB4-Akt1-mediated lamin A/C phosphorylation and nuclear softening. These results may provide a potential treatment strategy for tumor metastasis by targeting nuclear stiffness in patients with cancer, particularly CRC.


Colorectal Neoplasms , Lamin Type A , Proto-Oncogene Proteins c-akt , Receptor, ErbB-4 , Signal Transduction , Colorectal Neoplasms/metabolism , Colorectal Neoplasms/pathology , Humans , Receptor, ErbB-4/metabolism , Receptor, ErbB-4/genetics , Proto-Oncogene Proteins c-akt/metabolism , Lamin Type A/metabolism , Animals , Cell Line, Tumor , Mice , Cell Nucleus/metabolism , Cell Movement , Male , Female , Phosphorylation , Neoplasm Metastasis , Mice, Nude
3.
Genome Biol ; 25(1): 121, 2024 May 13.
Article En | MEDLINE | ID: mdl-38741206

Multiomic droplet-based technologies allow different molecular modalities, such as chromatin accessibility and gene expression (scATAC-seq and scRNA-seq), to be probed in the same nucleus. We develop EmptyDropsMultiome, an approach that distinguishes true nuclei-containing droplets from background. Using simulations, we show that EmptyDropsMultiome has higher statistical power and accuracy than existing approaches, including CellRanger-arc and EmptyDrops. On real datasets, we observe that CellRanger-arc misses more than half of the nuclei identified by EmptyDropsMultiome and, moreover, is biased against certain cell types, some of which have a retrieval rate lower than 20%.


Single-Cell Analysis , Single-Cell Analysis/methods , Humans , Cell Nucleus/genetics , Cell Nucleus/metabolism , Chromatin/metabolism , Chromatin/genetics , Multiomics
5.
Nucleus ; 15(1): 2350182, 2024 Dec.
Article En | MEDLINE | ID: mdl-38738760

Long noncoding RNAs (LncRNAs) are key regulators of gene expression and can mediate their effects in both the nucleus and cytoplasm. Some of the best-characterized lncRNAs are localized within the nucleus, where they modulate the nuclear architecture and influence gene expression. In this review, we discuss the role of lncRNAs in nuclear architecture in the context of their gene regulatory functions in innate immunity. Here, we discuss various approaches to functionally characterize nuclear-localized lncRNAs and the challenges faced in the field.


Cell Nucleus , RNA, Long Noncoding , RNA, Long Noncoding/genetics , RNA, Long Noncoding/metabolism , Humans , Cell Nucleus/metabolism , Cell Nucleus/genetics , Animals , Immunity, Innate , Gene Expression Regulation
6.
J Nanobiotechnology ; 22(1): 261, 2024 May 17.
Article En | MEDLINE | ID: mdl-38760744

Delayed repair of fractures seriously impacts patients' health and significantly increases financial burdens. Consequently, there is a growing clinical demand for effective fracture treatment. While current materials used for fracture repair have partially addressed bone integrity issues, they still possess limitations. These challenges include issues associated with autologous material donor sites, intricate preparation procedures for artificial biomaterials, suboptimal biocompatibility, and extended degradation cycles, all of which are detrimental to bone regeneration. Hence, there is an urgent need to design a novel material with a straightforward preparation method that can substantially enhance bone regeneration. In this context, we developed a novel nanoparticle, mPPTMP195, to enhance the bioavailability of TMP195 for fracture treatment. Our results demonstrate that mPPTMP195 effectively promotes the differentiation of bone marrow mesenchymal stem cells into osteoblasts while inhibiting the differentiation of bone marrow mononuclear macrophages into osteoclasts. Moreover, in a mouse femur fracture model, mPPTMP195 nanoparticles exhibited superior therapeutic effects compared to free TMP195. Ultimately, our study highlights that mPPTMP195 accelerates fracture repair by preventing HDAC4 translocation from the cytoplasm to the nucleus, thereby activating the NRF2/HO-1 signaling pathway. In conclusion, our study not only proposes a new strategy for fracture treatment but also provides an efficient nano-delivery system for the widespread application of TMP195 in various other diseases.


Cell Differentiation , Histone Deacetylases , Mesenchymal Stem Cells , Nanoparticles , Animals , Mice , Mesenchymal Stem Cells/drug effects , Mesenchymal Stem Cells/metabolism , Nanoparticles/chemistry , Cell Differentiation/drug effects , Histone Deacetylases/metabolism , NF-E2-Related Factor 2/metabolism , Mice, Inbred C57BL , Osteoclasts/drug effects , Osteoclasts/metabolism , Osteoblasts/drug effects , Signal Transduction/drug effects , Heme Oxygenase-1/metabolism , Male , Bone Regeneration/drug effects , Osteogenesis/drug effects , Cell Nucleus/metabolism , Fracture Healing/drug effects , Humans , Membrane Proteins
7.
Curr Protoc ; 4(5): e1042, 2024 May.
Article En | MEDLINE | ID: mdl-38767195

Biochemical fractionation is a technique used to isolate and separate distinct cellular compartments, critical for dissecting cellular mechanisms and molecular pathways. Herein we outline a biochemical fraction methodology for isolation of ultra-pure nuclei and cytoplasm. This protocol utilizes hypotonic lysis buffer to suspend cells, coupled with a calibrated centrifugation strategy, for enhanced separation of cytoplasm from the nuclear fraction. Subsequent purification steps ensure the integrity of the isolated nuclear fraction. Overall, this method facilitates accurate protein localization, essential for functional studies, demonstrating its efficacy in separating cellular compartments. © 2024 The Authors. Current Protocols published by Wiley Periodicals LLC. Basic Protocol: Biochemical fractionation Support Protocol 1: Protein quantification using Bradford assay Support Protocol 2: SDS/PAGE and Western blotting.


Cell Fractionation , Cell Nucleus , Cytoplasm , Cytoplasm/metabolism , Cytoplasm/chemistry , Cell Nucleus/metabolism , Cell Nucleus/chemistry , Cell Fractionation/methods , Humans , Electrophoresis, Polyacrylamide Gel , Blotting, Western
8.
Int J Mol Sci ; 25(9)2024 Apr 30.
Article En | MEDLINE | ID: mdl-38732093

The chromatin organization and its dynamic remodeling determine its accessibility and sensitivity to DNA damage oxidative stress, the main source of endogenous DNA damage. We studied the role of the VRK1 chromatin kinase in the response to oxidative stress. which alters the nuclear pattern of histone epigenetic modifications and phosphoproteome pathways. The early effect of oxidative stress on chromatin was studied by determining the levels of 8-oxoG lesions and the alteration of the epigenetic modification of histones. Oxidative stress caused an accumulation of 8-oxoG DNA lesions that were increased by VRK1 depletion, causing a significant accumulation of DNA strand breaks detected by labeling free 3'-DNA ends. In addition, oxidative stress altered the pattern of chromatin epigenetic marks and the nuclear phosphoproteome pathways that were impaired by VRK1 depletion. Oxidative stress induced the acetylation of H4K16ac and H3K9 and the loss of H3K4me3. The depletion of VRK1 altered all these modifications induced by oxidative stress and resulted in losses of H4K16ac and H3K9ac and increases in the H3K9me3 and H3K4me3 levels. All these changes were induced by the oxidative stress in the epigenetic pattern of histones and impaired by VRK1 depletion, indicating that VRK1 plays a major role in the functional reorganization of chromatin in the response to oxidative stress. The analysis of the nuclear phosphoproteome in response to oxidative stress detected an enrichment of the phosphorylated proteins associated with the chromosome organization and chromatin remodeling pathways, which were significantly decreased by VRK1 depletion. VRK1 depletion alters the histone epigenetic pattern and nuclear phosphoproteome pathways in response to oxidative stress. The enzymes performing post-translational epigenetic modifications are potential targets in synthetic lethality strategies for cancer therapies.


Epigenesis, Genetic , Histones , Oxidative Stress , Protein Serine-Threonine Kinases , Humans , Histones/metabolism , Protein Serine-Threonine Kinases/metabolism , Protein Serine-Threonine Kinases/genetics , Proteome/metabolism , Intracellular Signaling Peptides and Proteins/metabolism , Intracellular Signaling Peptides and Proteins/genetics , Phosphoproteins/metabolism , Phosphoproteins/genetics , DNA Damage , Cell Nucleus/metabolism , Chromatin/metabolism , Chromatin/genetics , Cell Line, Tumor , Acetylation , Protein Processing, Post-Translational
9.
J Cell Biol ; 223(6)2024 Jun 03.
Article En | MEDLINE | ID: mdl-38709216

Autophagy is an essential degradation program required for cell homeostasis. Among its functions is the engulfment and destruction of cytosolic pathogens, termed xenophagy. Not surprisingly, many pathogens use various strategies to circumvent or co-opt autophagic degradation. For poxviruses, it is known that infection activates autophagy, which however is not required for successful replication. Even though these complex viruses replicate exclusively in the cytoplasm, autophagy-mediated control of poxvirus infection has not been extensively explored. Using the prototypic poxvirus, vaccinia virus (VACV), we show that overexpression of the xenophagy receptors p62, NDP52, and Tax1Bp1 restricts poxvirus infection. While NDP52 and Tax1Bp1 were degraded, p62 initially targeted cytoplasmic virions before being shunted to the nucleus. Nuclear translocation of p62 was dependent upon p62 NLS2 and correlated with VACV kinase mediated phosphorylation of p62 T269/S272. This suggests that VACV targets p62 during the early stages of infection to avoid destruction and further implies that poxviruses exhibit multi-layered control of autophagy to facilitate cytoplasmic replication.


Autophagy , Cell Nucleus , Sequestosome-1 Protein , Vaccinia virus , Humans , Active Transport, Cell Nucleus , Cell Nucleus/metabolism , Cell Nucleus/virology , HEK293 Cells , HeLa Cells , Nuclear Proteins/metabolism , Nuclear Proteins/genetics , Phosphorylation , Sequestosome-1 Protein/metabolism , Sequestosome-1 Protein/genetics , Vaccinia/metabolism , Vaccinia/virology , Vaccinia/genetics , Vaccinia virus/metabolism , Vaccinia virus/genetics , Virus Replication
10.
Nat Commun ; 15(1): 3901, 2024 May 09.
Article En | MEDLINE | ID: mdl-38724505

Activation of the NF-κB pathway is strictly regulated to prevent excessive inflammatory and immune responses. In a well-known negative feedback model, IκBα-dependent NF-κB termination is a delayed response pattern in the later stage of activation, and the mechanisms mediating the rapid termination of active NF-κB remain unclear. Here, we showed IκBα-independent rapid termination of nuclear NF-κB mediated by CLK2, which negatively regulated active NF-κB by phosphorylating the RelA/p65 subunit of NF-κB at Ser180 in the nucleus to limit its transcriptional activation through degradation and nuclear export. Depletion of CLK2 increased the production of inflammatory cytokines, reduced viral replication and increased the survival of the mice. Mechanistically, CLK2 phosphorylated RelA/p65 at Ser180 in the nucleus, leading to ubiquitin‒proteasome-mediated degradation and cytoplasmic redistribution. Importantly, a CLK2 inhibitor promoted cytokine production, reduced viral replication, and accelerated murine psoriasis. This study revealed an IκBα-independent mechanism of early-stage termination of NF-κB in which phosphorylated Ser180 RelA/p65 turned off posttranslational modifications associated with transcriptional activation, ultimately resulting in the degradation and nuclear export of RelA/p65 to inhibit excessive inflammatory activation. Our findings showed that the phosphorylation of RelA/p65 at Ser180 in the nucleus inhibits early-stage NF-κB activation, thereby mediating the negative regulation of NF-κB.


Cytoplasm , NF-KappaB Inhibitor alpha , NF-kappa B , Protein-Tyrosine Kinases , Transcription Factor RelA , Animals , Phosphorylation , NF-KappaB Inhibitor alpha/metabolism , NF-KappaB Inhibitor alpha/genetics , Mice , Transcription Factor RelA/metabolism , Humans , Protein-Tyrosine Kinases/metabolism , Protein-Tyrosine Kinases/genetics , NF-kappa B/metabolism , Cytoplasm/metabolism , Proteolysis , Cell Nucleus/metabolism , Virus Replication , HEK293 Cells , Signal Transduction , Mice, Inbred C57BL , Cytokines/metabolism , Active Transport, Cell Nucleus , Protein Serine-Threonine Kinases
11.
Proc Natl Acad Sci U S A ; 121(22): e2314166121, 2024 May 28.
Article En | MEDLINE | ID: mdl-38768348

The nonstructural protein 1 (Nsp1) of SARS-CoV-2 (Severe Acute Respiratory Syndrome Coronavirus 2) is a virulence factor that targets multiple cellular pathways to inhibit host gene expression and antiviral response. However, the underlying mechanisms of the various Nsp1-mediated functions and their contributions to SARS-CoV-2 virulence remain unclear. Among the targets of Nsp1 is the mRNA (messenger ribonucleic acid) export receptor NXF1-NXT1, which mediates nuclear export of mRNAs from the nucleus to the cytoplasm. Based on Nsp1 crystal structure, we generated mutants on Nsp1 surfaces and identified an acidic N-terminal patch that is critical for interaction with NXF1-NXT1. Photoactivatable Nsp1 probe reveals the RNA Recognition Motif (RRM) domain of NXF1 as an Nsp1 N-terminal binding site. By mutating the Nsp1 N-terminal acidic patch, we identified a separation-of-function mutant of Nsp1 that retains its translation inhibitory function but substantially loses its interaction with NXF1 and reverts Nsp1-mediated mRNA export inhibition. We then generated a recombinant (r)SARS-CoV-2 mutant on the Nsp1 N-terminal acidic patch and found that this surface is key to promote NXF1 binding and inhibition of host mRNA nuclear export, viral replication, and pathogenicity in vivo. Thus, these findings provide a mechanistic understanding of Nsp1-mediated mRNA export inhibition and establish the importance of this pathway in the virulence of SARS-CoV-2.


Active Transport, Cell Nucleus , COVID-19 , Nucleocytoplasmic Transport Proteins , RNA, Messenger , RNA-Binding Proteins , SARS-CoV-2 , Viral Nonstructural Proteins , Humans , SARS-CoV-2/metabolism , SARS-CoV-2/pathogenicity , SARS-CoV-2/genetics , Viral Nonstructural Proteins/metabolism , Viral Nonstructural Proteins/genetics , Viral Nonstructural Proteins/chemistry , RNA, Messenger/genetics , RNA, Messenger/metabolism , Nucleocytoplasmic Transport Proteins/metabolism , Nucleocytoplasmic Transport Proteins/genetics , Animals , COVID-19/virology , COVID-19/metabolism , RNA-Binding Proteins/metabolism , RNA-Binding Proteins/genetics , Virus Replication , Cell Nucleus/metabolism , Vero Cells , Virulence , Chlorocebus aethiops , HEK293 Cells
12.
Nat Commun ; 15(1): 4328, 2024 May 21.
Article En | MEDLINE | ID: mdl-38773155

Parental experiences can affect the phenotypic plasticity of offspring. In locusts, the population density that adults experience regulates the number and hatching synchrony of their eggs, contributing to locust outbreaks. However, the pathway of signal transmission from parents to offspring remains unclear. Here, we find that transcription factor Forkhead box protein N1 (FOXN1) responds to high population density and activates the polypyrimidine tract-binding protein 1 (Ptbp1) in locusts. FOXN1-PTBP1 serves as an upstream regulator of miR-276, a miRNA to control egg-hatching synchrony. PTBP1 boosts the nucleo-cytoplasmic transport of pre-miR-276 in a "CU motif"-dependent manner, by collaborating with the primary exportin protein exportin 5 (XPO5). Enhanced nuclear export of pre-miR-276 elevates miR-276 expression in terminal oocytes, where FOXN1 activates Ptbp1 and leads to egg-hatching synchrony in response to high population density. Additionally, PTBP1-prompted nuclear export of pre-miR-276 is conserved in insects, implying a ubiquitous mechanism to mediate transgenerational effects.


Active Transport, Cell Nucleus , Grasshoppers , MicroRNAs , Polypyrimidine Tract-Binding Protein , Animals , MicroRNAs/metabolism , MicroRNAs/genetics , Polypyrimidine Tract-Binding Protein/metabolism , Polypyrimidine Tract-Binding Protein/genetics , Grasshoppers/genetics , Grasshoppers/metabolism , Female , Forkhead Transcription Factors/metabolism , Forkhead Transcription Factors/genetics , Ovum/metabolism , Insect Proteins/metabolism , Insect Proteins/genetics , Cell Nucleus/metabolism , Oocytes/metabolism
13.
Proc Natl Acad Sci U S A ; 121(19): e2401341121, 2024 May 07.
Article En | MEDLINE | ID: mdl-38696466

Neurotropic alphaherpesviruses, including herpes simplex virus type 1 (HSV-1), recruit microtubule motor proteins to invade cells. The incoming viral particle traffics to nuclei in a two-step process. First, the particle uses the dynein-dynactin motor to sustain transport to the centrosome. In neurons, this step is responsible for long-distance retrograde axonal transport and is an important component of the neuroinvasive property shared by these viruses. Second, a kinesin-dependent mechanism redirects the particle from the centrosome to the nucleus. We have reported that the kinesin motor used during the second step of invasion is assimilated into nascent virions during the previous round of infection. Here, we report that the HSV-1 pUL37 tegument protein suppresses the assimilated kinesin-1 motor during retrograde axonal transport. Region 2 (R2) of pUL37 was required for suppression and functioned independently of the autoinhibitory mechanism native to kinesin-1. Furthermore, the motor domain and proximal coiled coil of kinesin-1 were sufficient for HSV-1 assimilation, pUL37 suppression, and nuclear trafficking. pUL37 localized to the centrosome, the site of assimilated kinesin-1 activation during infection, when expressed in cells in the absence of other viral proteins; however, pUL37 did not suppress kinesin-1 in this context. These results indicate that the pUL37 tegument protein spatially and temporally regulates kinesin-1 via the amino-terminal motor region in the context of the incoming viral particle.


Herpesvirus 1, Human , Kinesins , Viral Structural Proteins , Kinesins/metabolism , Herpesvirus 1, Human/physiology , Herpesvirus 1, Human/metabolism , Humans , Animals , Axonal Transport/physiology , Chlorocebus aethiops , Centrosome/metabolism , Neurons/metabolism , Neurons/virology , Vero Cells , Cell Nucleus/metabolism , Cell Nucleus/virology
14.
Biochim Biophys Acta Mol Basis Dis ; 1870(5): 167224, 2024 Jun.
Article En | MEDLINE | ID: mdl-38723872

BACKGROUND: Pentamethylquercetin (PMQ) is a natural polymethyl flavonoid that possesses anti-apoptotic and other biological properties. Abdominal aortic aneurysm (AAA), a fatal vascular disease with a high risk of rupture, is associated with phenotypic switching and apoptosis of medial vascular smooth muscle cells (VSMCs). This study aimed to investigate the protective effects of PMQ on the development of AAA and the underlying mechanism. METHODS: ApoE-/- mice were continuously infused with angiotensin II (Ang II) for 4 weeks to develop the AAA model. Intragastric administration of PMQ was initiated 5 days before Ang II infusion and continued for 4 weeks. In vitro, VSMCs were cultured and pretreated with PMQ, stimulated with Ang II. Real-time PCR, western blotting, and immunofluorescence staining were used to examine the roles and mechanisms of PMQ on the phenotypic switching and apoptosis of VSMCs. RESULTS: PMQ dose-dependently reduced the incidence of Ang II-induced AAA, aneurysm diameter enlargement, elastin degradation, VSMCs phenotypic switching and apoptosis. Furthermore, PMQ also inhibited phenotypic switching and apoptosis in Ang II-stimulated VSMCs. PMQ exerted protective effects by regulating the C/EBPß/PTEN/AKT/GSK-3ß axis. AAV-mediated overexpression of PTEN reduced the therapeutic effects of PMQ in the AAA model mice, suggesting that the effects of PMQ on Ang II-mediated AAA formation were related to the PTEN/AKT/GSK-3ß axis. PMQ inhibited VSMCs phenotypic switching and apoptosis by bounding to C/EBPß at Lys253 with hydrogen bond to regulate C/EBPß nuclear translocation and PTEN/AKT/GSK-3ß axis, thereby inhibiting Ang II-induced AAA formation. CONCLUSIONS: Pentamethylquercetin inhibits angiotensin II-induced abdominal aortic aneurysm formation by bounding to C/EBPß at Lys253. Therefore, PMQ prevents the formation of AAA and reduces the incidence of AAA.


Angiotensin II , Aortic Aneurysm, Abdominal , Apoptosis , Muscle, Smooth, Vascular , Quercetin , Animals , Aortic Aneurysm, Abdominal/metabolism , Aortic Aneurysm, Abdominal/pathology , Aortic Aneurysm, Abdominal/prevention & control , Aortic Aneurysm, Abdominal/chemically induced , Aortic Aneurysm, Abdominal/drug therapy , Angiotensin II/pharmacology , Mice , Quercetin/analogs & derivatives , Quercetin/pharmacology , Apoptosis/drug effects , Muscle, Smooth, Vascular/metabolism , Muscle, Smooth, Vascular/drug effects , Muscle, Smooth, Vascular/pathology , Male , Myocytes, Smooth Muscle/metabolism , Myocytes, Smooth Muscle/drug effects , Myocytes, Smooth Muscle/pathology , Disease Models, Animal , PTEN Phosphohydrolase/metabolism , PTEN Phosphohydrolase/genetics , Proto-Oncogene Proteins c-akt/metabolism , Mice, Inbred C57BL , Glycogen Synthase Kinase 3 beta/metabolism , Signal Transduction/drug effects , Cells, Cultured , Cell Nucleus/metabolism , Cell Nucleus/drug effects
15.
Ann Med ; 56(1): 2282184, 2024 Dec.
Article En | MEDLINE | ID: mdl-38738386

AURKA is a threonine or serine kinase that needs to be activated by TPX2, Bora and other factors. AURKA is located on chromosome 20 and is amplified or overexpressed in many human cancers, such as breast cancer. AURKA regulates some basic cellular processes, and this regulation is realized via the phosphorylation of downstream substrates. AURKA can function in either the cytoplasm or the nucleus. It can promote the transcription and expression of oncogenes together with other transcription factors in the nucleus, including FoxM1, C-Myc, and NF-κB. In addition, it also sustains carcinogenic signaling, such as N-Myc and Wnt signaling. This article will focus on the role of AURKA in the nucleus and its carcinogenic characteristics that are independent of its kinase activity to provide a theoretical explanation for mechanisms of resistance to kinase inhibitors and a reference for future research on targeted inhibitors.


AURKA plays an important role in the control of the proliferation, invasion, cell cycle regulation and self-renewal of cancer stem cells.Small molecule kinase inhibitors targeting AURKA have been developed, but the overall response rate of patients in clinical trials is not ideal, prompting us to pay attention to the non-kinase activity of AURKA.This review focuses on the nuclear function of AURKA and its oncogenic properties independent of kinase activity, demonstrating that the nuclear substrate of AURKA and the remote allosteric site of the kinase may be targets of anticancer therapy.


Aurora Kinase A , Carcinogenesis , Cell Nucleus , Humans , Aurora Kinase A/metabolism , Carcinogenesis/genetics , Carcinogenesis/metabolism , Cell Nucleus/metabolism , Neoplasms/genetics , Neoplasms/metabolism , Signal Transduction , Gene Expression Regulation, Neoplastic , Protein Kinase Inhibitors/pharmacology , Animals
16.
Nucleus ; 15(1): 2351957, 2024 Dec.
Article En | MEDLINE | ID: mdl-38753956

Abnormal cell nuclear shapes are hallmarks of diseases, including progeria, muscular dystrophy, and many cancers. Experiments have shown that disruption of heterochromatin and increases in euchromatin lead to nuclear deformations, such as blebs and ruptures. However, the physical mechanisms through which chromatin governs nuclear shape are poorly understood. To investigate how heterochromatin and euchromatin might govern nuclear morphology, we studied chromatin microphase separation in a composite coarse-grained polymer and elastic shell simulation model. By varying chromatin density, heterochromatin composition, and heterochromatin-lamina interactions, we show how the chromatin phase organization may perturb nuclear shape. Increasing chromatin density stabilizes the lamina against large fluctuations. However, increasing heterochromatin levels or heterochromatin-lamina interactions enhances nuclear shape fluctuations by a "wetting"-like interaction. In contrast, fluctuations are insensitive to heterochromatin's internal structure. Our simulations suggest that peripheral heterochromatin accumulation could perturb nuclear morphology, while nuclear shape stabilization likely occurs through mechanisms other than chromatin microphase organization.


Cell Nucleus , Chromatin , Heterochromatin , Cell Nucleus/metabolism , Heterochromatin/metabolism , Heterochromatin/chemistry , Chromatin/metabolism , Chromatin/chemistry , Polymers/chemistry , Polymers/metabolism , Euchromatin/metabolism , Euchromatin/chemistry , Humans , Phase Separation
17.
Nucleus ; 15(1): 2353249, 2024 Dec.
Article En | MEDLINE | ID: mdl-38753965

In the nucleus, the VRK1 Ser-Thr kinase is distributed in nucleoplasm and chromatin, where it has different roles. VRK1 expression increases in response to mitogenic signals. VRK1 regulates cyclin D1 expression at G0 exit and facilitates chromosome condensation at the end of G2 and G2/M progression to mitosis. These effects are mediated by the phosphorylation of histone H3 at Thr3 by VRK1, and later in mitosis by haspin. VRK1 regulates the apigenetic patterns of histones in processes requiring chromating remodeling, such as transcription, replication and DNA repair. VRK1 is overexpressed in tumors, facilitating tumor progression and resistance to genotoxic treatments. VRK1 also regulates the organization of Cajal bodies assembled on coilin, which are necessary for the assembly of different types of RNP complexes. VRK1 pathogenic variants cuase defects in Cajal bodies, functionally altering neurons with long axons and leading to neurological diseases, such as amyotrophic laterla sclerosis, spinal muscular atrophy, distal hereditay motor neuropathies and Charcot-Marie-Tooth.


Protein Serine-Threonine Kinases , Humans , Protein Serine-Threonine Kinases/metabolism , Protein Serine-Threonine Kinases/genetics , Cell Nucleus/metabolism , Coiled Bodies/metabolism , Animals , Intracellular Signaling Peptides and Proteins/metabolism , Intracellular Signaling Peptides and Proteins/genetics
18.
Nat Commun ; 15(1): 4095, 2024 May 15.
Article En | MEDLINE | ID: mdl-38750021

Polymerized ß-actin may provide a structural basis for chromatin accessibility and actin transport into the nucleus can guide mesenchymal stem cell (MSC) differentiation. Using MSC, we show that using CK666 to inhibit Arp2/3 directed secondary actin branching results in decreased nuclear actin structure, and significantly alters chromatin access measured with ATACseq at 24 h. The ATAC-seq results due to CK666 are distinct from those caused by cytochalasin D (CytoD), which enhances nuclear actin structure. In addition, nuclear visualization shows Arp2/3 inhibition decreases pericentric H3K9me3 marks. CytoD, alternatively, induces redistribution of H3K27me3 marks centrally. Such alterations in chromatin landscape are consistent with differential gene expression associated with distinctive differentiation patterns. Further, knockdown of the non-enzymatic monomeric actin binding protein, Arp4, leads to extensive chromatin unpacking, but only a modest increase in transcription, indicating an active role for actin-Arp4 in transcription. These data indicate that dynamic actin remodeling can regulate chromatin interactions.


Actin-Related Protein 2-3 Complex , Actins , Cell Nucleus , Chromatin , Mesenchymal Stem Cells , Actins/metabolism , Chromatin/metabolism , Cell Nucleus/metabolism , Actin-Related Protein 2-3 Complex/metabolism , Actin-Related Protein 2-3 Complex/genetics , Mesenchymal Stem Cells/metabolism , Mesenchymal Stem Cells/cytology , Animals , Cell Differentiation , Cytochalasin D/pharmacology , Histones/metabolism , Humans , Microfilament Proteins/metabolism , Microfilament Proteins/genetics , Mice , Chromatin Assembly and Disassembly
19.
Mol Cell ; 84(9): 1635-1636, 2024 May 02.
Article En | MEDLINE | ID: mdl-38701740

In a recent publication in Nature, Xu et al.1 discovered a role of CRL5-SPSB3 ubiquitin ligase in promoting ubiquitination and degradation of nuclear cGAS, which prevents aberrant cGAS activation by genomic DNA and contributes to the maintenance of immune homeostasis.


Homeostasis , Nucleotidyltransferases , Ubiquitination , Nucleotidyltransferases/metabolism , Nucleotidyltransferases/genetics , Humans , Ubiquitin-Protein Ligases/metabolism , Ubiquitin-Protein Ligases/genetics , Cell Nucleus/metabolism , Proteolysis , Animals
20.
Cell Stem Cell ; 31(5): 583-585, 2024 May 02.
Article En | MEDLINE | ID: mdl-38701751

How nuclear RNA homeostasis impacts cellular functions remains elusive. In this issue of Cell Stem Cell, Han et al.1 utilized a controllable protein degradation system targeting EXOSC2 to perturb RNA homeostasis in mouse pluripotent embryonic stem cells, revealing its vital role in orchestrating crucial nuclear events for cellular fitness.


Homeostasis , RNA, Nuclear , Animals , Mice , RNA, Nuclear/metabolism , RNA, Nuclear/genetics , Exosome Multienzyme Ribonuclease Complex/metabolism , Exosome Multienzyme Ribonuclease Complex/genetics , Cell Nucleus/metabolism , Mouse Embryonic Stem Cells/metabolism , Mouse Embryonic Stem Cells/cytology , Humans , RNA-Binding Proteins/metabolism , RNA-Binding Proteins/genetics , RNA/metabolism , Pluripotent Stem Cells/metabolism , Pluripotent Stem Cells/cytology
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