Laminopathies and A-type lamin-associated signalling pathways (original) (raw)
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Nuclear envelope proteins and chromatin arrangement: a pathogenic mechanism for laminopathies
European journal of histochemistry : EJH
The involvement of the nuclear envelope in the modulation of chromatin organization is strongly suggested by the increasing number of human diseases due to mutations of nuclear envelope proteins. A common feature of these diseases, named laminopathies, is the occurrence of major chromatin defects. We previously reported that cells from laminopathic patients show an altered nuclear profile, and loss or detachment of heterochromatin from the nuclear envelope. Recent evidence indicates that processing of the lamin A precursor is altered in laminopathies featuring pre-mature aging and/or lipodystrophy phenotype. In these cases, pre-lamin A is accumulated in the nucleus and heterochromatin is severely disorganized. Here we report evidence indicating that pre-lamin A is mis-localized in the nuclei of Emery-Dreifuss muscular dystrophy fibroblasts, either bearing lamin A/C or emerin mutations. Abnormal pre-lamin A-containing structures are formed following treatment with a farnesyl-transfer...
Review: Nuclear Lamins—Structural Proteins with Fundamental Functions
Journal of Structural Biology, 2000
The nuclear lamina is located between the inner nuclear membrane and the peripheral chromatin. It is composed of both peripheral and integral membrane proteins, including lamins and lamina-associated proteins. Lamins can interact with one another, with lamina-associated proteins, with nuclear scaffold proteins, and with chromatin. Likewise, most of the lamina-associated proteins are likely to interact directly with chromatin. The nuclear lamina is required for proper cell cycle regulation, chromatin organization, DNA replication, cell differentiation, and apoptosis. Mutations in proteins of the nuclear lamina can disrupt these activities and cause genetic diseases. The structure and assembly of the nuclear lamina proteins and their roles in chromatin organization and cell cycle regulation were recently reviewed. In this review, we discuss the roles of the nuclear lamina in DNA replication and apoptosis and analyze how mutations in nuclear lamina proteins might cause genetic diseases. 2000
Mapping of protein- and chromatin-interactions at the nuclear lamina
Nucleus, 2010
The nuclear envelope and the lamina define the nuclear periphery and are implicated in many nuclear processes including chromatin organization, transcription and DNA replication. Mutations in lamin A proteins, major components of the lamina, interfere with these functions and cause a set of phenotypically diverse diseases referred to as laminopathies. The phenotypic diversity of laminopathies is thought to be the result of alterations in specific protein- and chromatin interactions due to lamin A mutations. Systematic identification of lamin A-protein and -chromatin interactions will be critical to uncover the molecular etiology of laminopathies. Here we summarize and critically discuss recent technology to analyze lamina-protein and-chromatin interactions.
Dynamic interactions of nuclear lamina proteins with chromatin and transcriptional machinery
Cellular and Molecular Life Sciences CMLS, 2003
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
The Journal of cell biology, 2015
Nuclear organization has been implicated in regulating gene activity. Recently, large developmentally regulated regions of the genome dynamically associated with the nuclear lamina have been identified. However, little is known about how these lamina-associated domains (LADs) are directed to the nuclear lamina. We use our tagged chromosomal insertion site system to identify small sequences from borders of fibroblast-specific variable LADs that are sufficient to target these ectopic sites to the nuclear periphery. We identify YY1 (Ying-Yang1) binding sites as enriched in relocating sequences. Knockdown of YY1 or lamin A/C, but not lamin A, led to a loss of lamina association. In addition, targeted recruitment of YY1 proteins facilitated ectopic LAD formation dependent on histone H3 lysine 27 trimethylation and histone H3 lysine di- and trimethylation. Our results also reveal that endogenous loci appear to be dependent on lamin A/C, YY1, H3K27me3, and H3K9me2/3 for maintenance of lami...
Trends in Biochemical Sciences, 2001
The main feature of eukaryotic cells is the nucleus, which enwraps the chromosomes and is the site of DNA replication, RNA transcription and processing, and ribosome assembly. The nuclear envelope (NE) is the boundary between the nucleus and cytoplasm. The NE is composed of the inner and outer nuclear membranes (INM and ONM, respectively), which are separated by a lumenal space continuous with the ER lumen. Communication between the nucleoplasm and cytoplasm takes place through pores in the nuclear envelope, where the inner and outer membranes join. Within these pores are nuclear pore complexes (NPCs), which mediate and regulate nuclear transport 1 . Underneath the INM is a meshwork of nuclear-specific intermediate filaments, termed the nuclear lamina, which includes lamin proteins plus a growing number of lamin-associated proteins 2,3 . Near the INM is the peripheral chromatin, a large proportion of which is heterochromatin .
A chromatin binding site in the tail domain of nuclear lamins that interacts with core histones
Journal of Cell Biology, 1995
Interaction of chromatin with the nuclear envelope and lamina is thought to help determine higher order chromosome organization in the interphase nucleus. Previous studies have shown that nuclear lamins bind chromatin directly. Here we have localized a chromatin binding site to the carboxyl-terminal tail domains of both A-and B-type mammalian lamins, and have characterized the biochemical properties of this binding in detail. Recombinant glutathione-S-transferase fusion proteins containing the tail domains of mammalian lamins C, BI, and B 2 were analyzed for their ability to associate with rat liver chromatin fragments immobi-lized on microtiter plate wells. We found that all three lamin tails specifically bind to chromatin with apparent Kds of 120-300 nM. By examining a series of deletion mutants, we have mapped the chromatin binding region of the lamin C tail to amino acids 396--430, a segment immediately adjacent to the rod domain. Furthermore, by analysis of chromatin subfractions, we found that core histones constitute the principal chromatin binding component for the lamin C tail. Through cooperativity, this lamin-histone interaction could be involved in specifying the high avidity attachment of chromatin to the nuclear envelope in vivo. T HE nuclear lamina is a filamentous protein meshwork that lines the nucleoplasmic surface of the nuclear envelope (NE) 1 (reviewed by . The lamina is thought to provide a structural framework for the NE and an anchoring site at the nuclear periphery for interphase chromosomes, and therefore could play a major role in interphase nuclear organization. The lamina consists of a polymeric assembly of nuclear lamins, members of the intermediate filament (IF) protein superfamily (see , as well as a number of less abundant lamina-associated polypeptides (discussed by . Vertebrate lamins are classified as A-or B-subtypes based on their sequence and biochemical properties. B-type lamins (lamins B1 and B2) are present in somatic cells throughout development, while A-type lamins (lamins A and C) are expressed only during or after terminal differentiation in most cells. Mam-