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PubMed2026

Small GTPase RAN-driven PNET2 oligomerization and phase separation at the nuclear lamina promote nuclear envelope integrity in plants.

The nuclear envelope is a fundamental organizer of eukaryotic cells, yet how plants regulate its architecture and integrity remains poorly understood. In this study, we identified the plant inner nuclear membrane protein PLANT NUCLEAR ENVELOPE TRANSMEMBRANE 2 (PNET2) as a scaffold that maintains nuclear envelope integrity and genome stability. Loss of PNET2 function compromises nuclear membrane structure and sensitizes cells to DNA damage, whereas overexpression drives aberrant nuclear membrane expansion. Biochemically, PNET2 cooperates with the nuclear lamin protein KAKU4 and CROWDED NUCLEI 1 within the nuclear lamina to promote nuclear membrane remodeling, a process driven by biomolecular condensate formation via their intrinsically disordered regions. We further uncovered a direct interaction between PNET2 and the small GTPase RAN. Structural modeling and biochemical analyses revealed that its active GTP-bound form stimulates PNET2 oligomerization, potentially promoting its phase separation to drive membrane expansion. Genetic analyses showed that PNET2 and RAN function in a shared pathway essential for nuclear membrane integrity. Together, our findings define a regulatory module that orchestrates GTPase signaling to sustain nuclear membrane homeostasis in plants, positioning PNET2 as a nexus linking membrane dynamics, nuclear lamina organization, and genome protection.

PNET2↗
PubMed1996

Nuclear lamina and nuclear matrix organization in sperm pronuclei assembled in Xenopus egg extract.

Nuclear lamina and matrices were prepared from sperm pronuclei assembled in Xenopus egg extracts using a fractionation and extraction procedure. Indirect immunofluorescence revealed that while chromatin was efficiently removed from nuclei during the extraction procedure, the distribution of lamins was unaffected. Consistent with this data, the amount of lamin B3, determined by immunoblotting, was not affected through the extraction procedure. Nuclear matrices were visualised in DGD sections by TEM. Within these sections filaments were observed both at the boundary of the nucleus (the lamina) and within the body of the nucleus (internal nuclear matrix filaments). To improve resolution, nuclear matrices were also prepared as whole mounts and viewed using field emission in lens scanning electron microscopy (FEISEM). This technique revealed two distinct networks of filaments. Filaments lying at the surface of nuclear matrices interconnected nuclear pores. These filaments were readily labelled with monoclonal anti-lamin B3 antibodies. Filaments lying within the body of the nuclear matrix were highly branched but were not readily labelled with antilamin B3 antibodies. Nuclear matrices were also prepared from sperm pronuclei assembled in lamin B3 depleted extracts. Using FEISEM, filaments were also detected in these preparations. However, these filaments were poorly organised and often appeared to aggregate. To confirm these results nuclear matrices were also observed as whole mounts using TEM. Nuclear matrices prepared from control nuclei contained a dense array of interconnected filaments. Many (but not all) of these filaments were labelled with anti-lamin B3 antibodies. In contrast, nuclear matrices prepared from "lamin depleted nuclei' contained poorly organised or aggregated filaments which were not specifically labelled with anti-lamin B3 antibodies.

Animals↗
PubMed2006

Characterization of the Drosophila melanogaster genome at the nuclear lamina.

The nuclear lamina binds chromatin in vitro and is thought to function in its organization, but genes that interact with it are unknown. Using an in vivo approach, we identified approximately 500 Drosophila melanogaster genes that interact with B-type lamin (Lam). These genes are transcriptionally silent and late replicating, lack active histone marks and are widely spaced. These factors collectively predict lamin binding behavior, indicating that the nuclear lamina integrates variant and invariant chromatin features. Consistently, proximity of genomic regions to the nuclear lamina is partly conserved between cell types, and induction of gene expression or active histone marks reduces Lam binding. Lam target genes cluster in the genome, and these clusters are coordinately expressed during development. This genome-wide analysis gives clear insight into the nature and dynamic behavior of the genome at the nuclear lamina, and implies that intergenic DNA functions in the global organization of chromatin in the nucleus.

Animals↗
PubMed1992

Assembly and cell cycle dynamics of the nuclear lamina.

The nuclear lamina is a karyoskeletal structure composed of intermediate filament type proteins. It underlies the inner nuclear membrane and confers mechanical stability to the nuclear envelope. In addition, it interacts with chromatin and may thereby participate in determining the three-dimensional organization of the interphase nucleus. During mitosis, the nuclear lamina is transiently disassembled, most probably through hyperphosphorylation of lamin proteins by the protein kinase p34cdc2, a key regulator of the eukaryotic cell cycle. Mitotic disassembly of the lamina is necessary but not sufficient for nuclear envelope breakdown. Electron microscopic analyses have begun to provide insights into the principles that govern lamina assembly in vitro, and sequence motifs required for targeting newly synthesized lamins to the nuclear envelope have been identified. Of particular interest, lamins were shown to undergo a type of hydrophobic modification known as isoprenylation. Finally, recent studies addressing the nature of lamin-chromatin interactions may provide the basis for elucidating the role of lamins in organizing the distribution of interphase chromatin.

Amino Acid Sequence↗
PubMed1988

Protein kinase activity associated with the nuclear lamina.

A nuclear lamina-enriched fraction from Ehrlich ascites tumor cells contains a tightly bound protein kinase activity, which phosphorylates in vitro the nuclear lamins, a 52-kilodalton protein, and several unknown minor components. The enzyme(s) is thermolabile, independent of Ca2+ and cAMP, and inhibited by quercetin. After treatment with 4 M urea it remains bound to the nuclear lamina in an active state, but it is irreversibly inactivated in 6 M urea. The lamin proteins are phosphorylated on serine residues. Their two-dimensional phosphopeptide maps show multiple phosphorylation sites and a considerable similarity to the phosphopeptide maps of lamins labeled in vivo. Photoaffinity labeling experiments revealed several polypeptide fractions in the nuclear lamina fraction that are candidates for the protein kinase(s).

Animals↗
PubMed1984

Organization and modulation of nuclear lamina structure.

The nuclear lamina is a protein meshwork associated with the nucleoplasmic surface of the inner nuclear membrane, that is suggested to be important for organizing nuclear envelope and interphase chromosome architecture. To investigate the structural organization of the lamina, we have analysed rat liver nuclear envelopes by various chemical extraction procedures. From these studies, we have defined conditions that yield a nuclear envelope subfraction that is both highly enriched in the lamina and devoid of pore complexes. This fraction contains mostly lamins A, B and C, the three major lamina polypeptides that are apparently arranged in a polymeric assembly. Our chemical extraction studies also indicate that lamin B has a stronger interaction with nuclear membranes than the other two lamins, and support the possibility that lamin B is important for attaching the lamina to the inner nuclear membrane. We have examined the synthesis and assembly of the lamins during interphase in tissue-culture cells to investigate lamina structure by a second approach. We found that all three lamins are synthesized at similar rates throughout the cell cycle in synchronized Chinese hamster ovary cells, and that their biosynthesis is not temporally coupled to DNA replication. Our studies indicate that newly synthesized lamins are rapidly assembled into an insoluble lamina structure but that the apparent half-time for lamina insertion differs for individual lamins. We have also observed that lamin A is synthesized as an apparent precursor molecule that is converted to mature lamin A only after integration into the lamina structure. The lamina is reversibly depolymerized during cell division, a process that may be mediated by enzymic phosphorylation of the lamins. To investigate this possibility further, we have analysed charge-altering modifications of the lamins on two-dimensional gels, and have found that phosphorylation is the only detectable modification of these proteins that occurs specifically during mitosis. Furthermore, we have determined that when the lamins are disassembled during metaphase, each lamin has approximately 2 moles of associated phosphate/mole lamin, a value that is four to sevenfold higher than the average interphase level. Considering this information, we discuss a model by which depolymerization and reassembly of the lamina can regulate the reversible disassembly of the nuclear envelope during mitosis.

Animals↗
PubMed1993

A possible association of nuclear lamina with chromatin.

The nuclear lamina associated with chromatin was examined by electron microscopy. Nuclei isolated from rat ascites hepatoma cells were swollen in 0.2 mM EDTA (pH 7.0) and broken by a homogenizer. The resulting nuclear fragments were dialyzed against 0.2 mM EDTA (pH 7.0) overnight, fixed in formalin and sedimented on grids by centrifugation, then stained with 2% uranyl acetate and rotary-shadowed with platinum-palladium. The nuclear lamina consists of two filaments, twisting together both the filaments associated with chromatin fiber. The single filament of nuclear lamina of about 31 nm in width forms certain rings of about 187 nm in diameter, taking a distance of about 0.37 micron in length between the neighbouring rings. Thus, the arrangement of rings was proposed a packing structure in conforming the nuclear laminar complex with chromatin.

Animals↗
PubMed2005

Nuclear envelope, nuclear lamina, and inherited disease.

The nuclear envelope is composed of the nuclear membranes, nuclear lamina, and nuclear pore complexes. In recent years, mutations in nuclear-envelope proteins have been shown to cause a surprisingly wide array of inherited diseases. While the mutant proteins are generally expressed in most or all differentiated somatic cells, many mutations cause fairly tissue-specific disorders. Perhaps the most dramatic case is that of mutations in A-type lamins, intermediate filament proteins associated with the inner nuclear membrane. Different mutations in the same lamin proteins have been shown to cause striated muscle diseases, partial lipodystrophy syndromes, a peripheral neuropathy, and disorders with features of severe premature aging. In this review, we summarize fundamental aspects of nuclear envelope structure and function, the inherited diseases caused by mutations in lamins and other nuclear envelope proteins, and possible pathogenic mechanisms.

Animals↗
PubMed2003

Dynamic interactions of nuclear lamina proteins with chromatin and transcriptional machinery.

The nuclear lamina is a filamentous nuclear structure intimately connected to the inner nuclear membrane. It is composed of lamins, which are also present in the nuclear interior, and lamin-associated proteins. The nuclear lamina is involved directly or indirectly in many nuclear activities, including DNA replication and transcription, nuclear and chromatin organization, cell cycle regulation, cell development and differentiation, nuclear migration and apoptosis. Mutations in nuclear lamina genes cause a wide range of heritable human diseases, the molecular mechanisms for which are not well understood. This review describes our current knowledge of interactions between nuclear lamina proteins and chromatin, chromatin-remodeling factors, specific transcription factors and RNA polymerase II transcription machinery. Recent studies provide new insights into the nature and regulation of these interactions and suggest additional roles for the nuclear lamina.

Animals↗
PubMed2003

The nuclear lamina and its functions in the nucleus.

The nuclear lamina is a structure near the inner nuclear membrane and the peripheral chromatin. It is composed of lamins, which are also present in the nuclear interior, and lamin-associated proteins. The increasing number of proteins that interact with lamins and the compound interactions between these proteins and chromatin-associated proteins make the nuclear lamina a highly complex but also a very exciting structure. The nuclear lamina is an essential component of metazoan cells. It is involved in most nuclear activities including DNA replication, RNA transcription, nuclear and chromatin organization, cell cycle regulation, cell development and differentiation, nuclear migration, and apoptosis. Specific mutations in nuclear lamina genes cause a wide range of heritable human diseases. These diseases include Emery-Dreifuss muscular dystrophy, limb girdle muscular dystrophy, dilated cardiomyopathy (DCM) with conduction system disease, familial partial lipodystrophy (FPLD), autosomal recessive axonal neuropathy (Charcot-Marie-Tooth disorder type 2, CMT2), mandibuloacral dysplasia (MAD), Hutchison Gilford Progeria syndrome (HGS), Greenberg Skeletal Dysplasia, and Pelger-Huet anomaly (PHA). Genetic analyses in Caenorhabditis elegans, Drosophila, and mice show new insights into the functions of the nuclear lamina, and recent structural analyses have begun to unravel the molecular structure and assembly of lamins and their associated proteins.

Animals↗
PubMed1992

Nucleoplasmic localization of prelamin A: implications for prenylation-dependent lamin A assembly into the nuclear lamina.

The synthesis of the nuclear lamina protein lamin A requires the prenylation-dependent processing of its precursor protein, prelamin A. Unlike p21ras, which undergoes similar initial posttranslational modifications, maturation of lamin A results in the proteolytic removal of the prenylated portion of the molecule. We have used an in vitro prenylation system to demonstrate the nature of the prenyl substituent on prelamin A to be a farnesyl group. Further, the in vitro farnesylation of prelamin A requires an intact cysteine-aliphatic-aliphatic-other (CAAX) amino acid sequence motif at its carboxyl terminus. The effect of blocking the prenylation of prelamin A on its localization and assembly into the nuclear lamina was investigated by indirect immunofluorescence. Expression of wild-type prelamin A in lovastatin-treated cells showed that nonprenylated prelamin A accumulated as nucleoplasmic particles. Upon addition of mevalonate to lovastatin-treated cells, the wild-type lamin A was incorporated into the lamina within 3 hr. Expression of a mutant lamin A in which the carboxyl-terminal 21 amino acids were deleted resulted in a lamin molecule that was directly assembled into the lamina. These results indicate that the carboxyl-terminal peptide of prelamin A blocks its proper assembly into the nuclear lamina and that the prenylation-initiated removal of this peptide can occur in the nucleus.

Animals↗
PubMed1992

Presence of a novel nuclear lamina protein in Raji cells.

In mammalian tissues, the nuclear lamina is composed of the major lamins A, B, and C, and minor lamins D/E. Although lamin B is present in all cell types, lamins A and C are absent from embryonic cells and most undifferentiated cells from hematopoietic lineage. We have investigated the nuclear lamina protein composition of the Raji cell line, lymphoblast-like cells established from a Burkitt lymphoma patient. Lamins A and C were confirmed absent by immunodetection and Northern blot analysis. Besides lamins B and D/E, a protein migrating around 71 kilodaltons was recognized by a serum directed against the nuclear lamina of BHK-21 fibroblasts. Cellular localization by sequential extraction established this 71-kilodalton protein as an exclusive component of the nuclear lamina fraction. These results indicate that the nuclear lamina has a more complex composition than previously thought to be the case for cells devoid of lamins A and C.

Animals↗
PubMed1999

The nuclear lamina: molecular organization and interaction with chromatin.

The nuclear lamina is located between the inner nuclear membrane and the peripheral chromatin. It is composed mainly of nuclear lamins and lamina-associated proteins. The nuclear lamina is involved in nuclear organization, cell cycle regulation, and differentiation. As such, impairment in its architecture and/or function leads to genetic diseases and apoptosis. This article describes the molecular organization of the nuclear lamins, their assembly into filaments, their distribution within the nucleus, and the complex network of interactions between them and other proteins of the inner nuclear membrane. Recent findings unraveled evidence for specific interactions between proteins of the nuclear lamina and the chromatin. These include interactions between nuclear lamins and core histones, Lamina Associated Polypeptide 2 (LAP2), and the Barrier to Autointegration Factor (BAF) and interactions between lamin B receptor (LBR) and the chromodomain protein HP1. Taken together, these studies attribute a role for both the nuclear lamins and the lamina-associated proteins, LAP2 and LBR, in nuclear organization and nuclear assembly.

Animals↗
PubMed2001

Transcriptional repression, apoptosis, human disease and the functional evolution of the nuclear lamina.

The number and complexity of genes encoding nuclear lamina proteins has increased during metazoan evolution. Emerging evidence reveals that transcriptional repressors such as the retinoblastoma protein, and apoptotic regulators such as CED-4, have functional and dynamic interactions with the lamina. The discovery that mutations in nuclear lamina proteins cause heritable tissue-specific diseases, including Emery-Dreifuss muscular dystrophy, is prompting a fresh look at the nuclear lamina to devise models that can account for its diverse functions and dynamics, and to understand its enigmatic structure.

Animals↗
PubMed2002

Reversible changes in the nuclear lamina induced by hyperthermia.

The nuclear matrix (NM) has been identified as a potential target for heat-induced cell killing. Previous studies have shown that heat-shock may significantly modulate lamin B content. Since changes in NM structure have often been accompanied by changes in protein composition, we investigated whether hyperthermia induced changes in nuclear lamina (NL) structure in non-tolerant and thermotolerant cells, and the implications of these changes on cell survival. Using indirect immunofluorescence techniques and confocal microscopy, we found that heating cells at 42 or 45.5 degrees C caused invaginations and other distortions of the peripheral NL. While hyperthermia did not alter the number or structure of internal lamin B foci, heat-induced alterations to the peripheral NL were dose-dependent. Interestingly, NL structure recovered with time after heating in cells that were destined to live or die. Thermotolerant cells heated at 45.5 degrees C showed similar initial changes in the NL compared to non-tolerant cells, but recovery occurred much faster. Taken together, these results suggest that the amount of initial damage to the peripheral NL is not correlated with heat-induced cell killing. However, the possibility that an increased rate of recovery might confer a survival advantage cannot be discounted.

Cell Death↗
PubMed1998

Nuclear envelope disassembly in mitotic extract requires functional nuclear pores and a nuclear lamina.

Using sea urchin embryonic and in-vitro-assembled nuclei incubated in sea urchin mitotic extract, I provide evidence for a requirement for functional nuclear pores and a nuclear lamina for nuclear envelope disassembly in vitro. In interphase gastrula nuclei, lamin B interacts with p56, an integral protein of inner nuclear membrane cross-reacting with antibodies to human lamin B receptor. Incubation of gastrula nuclei in mitotic cytosol containing an ATP-generating system rapidly induces hyperphosphorylation of p56 and lamin B. Subsequently, p56-lamin B interactions are weakened and the two proteins segregate into distinct nuclear envelope-derived vesicles upon disassembly of nuclear membranes and of the lamina. Nuclear disassembly is accompanied by chromatin condensation. Blocking nuclear pore function with wheat germ agglutinin or antibodies to nucleoporins prevents p56 and lamin B hyperphosphorylation, nuclear membrane breakdown and lamina solubilization. These events are not rescued by permeabilization of nuclear membranes to molecules of 150, 000 Mr with lysolecithin. In-vitro-assembled nuclei containing nuclear membranes with functional pores but no lamina do not disassemble in mitotic cytosol in spite of p56 hyperphosphorylation. Nuclear import of soluble lamin B and reformation of a lamina in interphase extract restores nuclear disassembly in mitotic cytosol. The data indicate a role for functional nuclear pores in nuclear disassembly in vitro. They show that p56 hyperphosphorylation is not sufficient for nuclear membrane disassembly in mitotic cytosol and argue that the nuclear lamina plays a critical role in nuclear disassembly at mitosis.

Adenosine Triphosphate↗
PubMed2002

Cytomegalovirus recruitment of cellular kinases to dissolve the nuclear lamina.

The passage of large-sized herpesviral capsids through the nuclear lamina and the inner nuclear membrane to leave the nucleus requires a dissolution of the nuclear lamina. Here, we report on the functions of M50/p35, a beta-herpesviral protein of murine cytomegalovirus. M50/p35 inserts into the inner nuclear membrane and is aggregated by a second viral protein, M53/p38, to form the capsid docking site. M50/p35 recruits the cellular protein kinase C for phosphorylation and dissolution of the nuclear lamina, suggesting that herpesviruses target a critical element of nuclear architecture.

Capsid↗
PubMed1997

Nuclear lamina assembly in the first cell cycle of rat liver regeneration.

The nuclear lamina is a fibrous structure at the nucleoplasmic surface of the inner nuclear membrane. Its assembly state is regulated by phosphorylation of its protein components, the lamins A, B, and C. The isoprenylation of the lamins is essential for their proper membrane anchoring and functionality. The content and the membrane association of nuclear lamins and the subcellular localization at light and electron microscopical levels were studied at different times of rat liver regeneration. This model for the good synchrony of the first cell cycle is particularly suited for the study of cell-cycle-dependent modifications and is particularly interesting for the increased protein prenylation found in S phase. The biochemical results show an increased lamin content in nuclear proteins in G1 phase and a decreased content in M phase, along with an enhanced cytosolic localization of A and C lamins at later stages. The morphological results show in M phase, also in nondividing cells, a decreased lamin-like immunoreactivity around the nucleus with an apparent nuclear lamina disassembly. These data emphasize the dynamic organization of nuclear lamina not only in mitosis but also in interphase. The reduction and partial solubilization of nuclear lamina in M phase suggest a reorganization of the nuclear envelope also in those cells that do not appear in mitosis but have replicated their DNA content that will result in a higher degree of polyploidy.

Animals↗