Over the past few years it has become evident that the intermediate filament proteins, the types A and B nuclear lamins, not only provide a structural framework for the nucleus, but are also essential for many aspects of normal nuclear function. Insights into lamin-related functions have been derived from studies of the remarkably large number of disease-causing mutations in the human lamin A gene. This review provides an up-to-date overview of the functions of nuclear lamins, emphasizing their roles in epigenetics, chromatin organization, DNA replication, transcription, and DNA repair. In addition, we discuss recent evidence supporting the importance of lamins in viral infections.In eukaryotic cells, chromatin is tightly packed in a highly organized fashion within a nucleus that is composed of two main compartments: the nucleoplasm and the nuclear envelope (NE). There are also subcompartments in the nucleus containing factors involved in essential nuclear functions such as DNA replication, transcription, and RNA splicing (Prasanth and Spector 2006;Spector 2006). The NE separates nuclear functions from cytoplasmic functions and at its inner surface it provides a docking site for chromatin. The major structural elements of the NE are the inner nuclear membrane (INM), the outer nuclear membrane (ONM), the nuclear pore complexes (NPCs), and the nuclear lamina. The lamina is comprised of a complex meshwork of proteins closely associated with the INM and attached to the periphery of NPCs and to chromatin (Fawcett 1966;Patrizi and Poger 1967;Aaronson and Blobel 1975). The main constituents of the lamina are the type V intermediate filament (IF) proteins, the nuclear lamins. Lamins are also found, in lower concentrations, distributed throughout the nucleoplasm. The organization of lamins at the nuclear periphery as well as within the nucleoplasm is influenced by numerous lamin-binding proteins (Dorner et al. 2007;Schirmer and Foisner 2007;Wagner and Krohne 2007).This review focuses on the role of nuclear lamins in the organization and regulation of chromatin in the interphase nucleus-specifically, the involvement of lamins in essential processes such as transcription, DNA replication, DNA repair, and various epigenetic phenomena involved in the regulation of euchromatin-heterochromatin transitions. Emphasis is also placed on the remarkable array of disease-causing mutations in the human lamin A gene, from which many of the most recent insights into lamin functions have been derived. In addition, we also discuss emerging ideas regarding the roles of lamins in viral infections. General properties of the nuclear laminsNuclear lamins were initially described as the major protein components of detergent-high salt resistant "lamina" fractions of rat liver and chicken erythrocyte nuclei (Aaronson and Blobel 1975;Gerace et al. 1978). Subsequently it was shown that they are members of the IF protein family (Aebi et al. 1986;Goldman et al. 1986;McKeon et al. 1986). Lamin genes are found in all metazoa examined to date, but are...
The nuclear lamins function in the regulation of replication, transcription, and epigenetic modifications of chromatin. However, the mechanisms responsible for these lamin functions are poorly understood. We demonstrate that A-and B-type lamins form separate, but interacting, stable meshworks in the lamina and have different mobilities in the nucleoplasm as determined by fluorescence correlation spectroscopy (FCS). [Keywords: Lamins; chromatin; RNA polymerase II transcription; chromosome organization] Supplemental material is available at http://www.genesdev.org. Silencing lamin B1 (LB1) expression dramatically increases the lamina meshwork size and the mobility of nucleoplasmic lamin A (LA). The changes in lamina mesh
Numerous mutations in the humancomprising the major structural components of the nuclear lamina, the fibrous meshwork underlying the inner nuclear membrane (1). They are major determinants of nuclear size and shape and are involved in essential functions such as DNA replication and transcription (1). Lamins A (LA) and C (LC) are alternatively spliced products of the LMNA gene, whereas lamins LB1 and LB2 are encoded by LMNB1 and LMNB2. Structurally, the lamins have a conserved central ␣-helical rod domain flanked by globular head and tail domains. The central rod is responsible for the formation of in-parallel and in-register coiled-coil dimers, the building blocks of lamin polymers. In vitro, lamin dimers form head-to-tail chains, which further interact laterally in an anti-parallel orientation to form highly ordered paracrystals (PCs) (2). However, little is known about the assembly of lamins into higher order structures in vivo.There are Ͼ250 mutations in human LMNA causing a wide range of diseases [for detail, see http//www.umd.be/LMNA/ and (3)]. Among these is the rare premature aging disease, Hutchinson-Gilford progeria syndrome (HGPS). HGPS children typically appear normal at birth, but show growth retardation before the age of 2 years. Further manifestations include loss of hair, lipodystrophy, sclerodermatous skin, osteolysis, and progressive atherosclerosis leading to death at an average age of 13 years due to myocardial infarcts and strokes (4). Most HGPS patients carry the 1824CϾT mutation (G608G), which activates a cryptic splice site resulting in the expression of LA with 50 amino acids deleted near its C terminus (LA⌬50/progerin) (5). As a result, LA⌬50/ progerin remains permanently farnesylated (6, 7), and its accumulation in patients' cells is correlated with the loss of heterochromatin and changes in histone methylation (1).In addition to 1824CϾT, there are 21 other LMNA mutations causing progeria (http://www.umd.be/LMNA/). Some of these are located in the central rod domain, where they could directly impact the assembly of lamins into dimers and higher order structures. Here, we have studied the alterations in nuclear architecture and chromatin organization in one of these mutations, 433GϾA (E145K), located in segment 1B of the central rod domain of LA/C (5). A patient bearing this mutation showed earlier onset cardiovascular defects, only partial loss of hair and ample s.c. fat (5). We show that fibroblasts derived from an E145K patient have severely misshapen nuclei and multiple defects in chromatin organization as reflected by centromere clustering and an abnormal distribution of telomeres throughout the cell cycle. These abnormalities are established during cell division as nuclei assemble in daughter cells. The results demonstrate that the nuclear changes in E145K progeria cells are significantly different from those seen in cells expressing LA⌬50/ progerin, and they also emphasize the essential role of lamins in establishing and maintaining nuclear architecture.
Age is the largest single risk factor for the development of cancer in mammals. Age-associated chromosomal changes, such as aneuploidy and telomere erosion, may be vitally involved in the initial steps of tumorigenesis. However, changes in gene expression specific for increased aneuploidy with age have not yet been characterized. Here, we address these questions by using a panel of fibroblast cell lines and lymphocyte cultures from young and old age groups. Oligonucleotide microarrays were used to characterize the expression of 14,500 genes. We measured telomere length and analyzed chromosome copy number changes and structural rearrangements by multicolor interphase fluorescence in situ hybridization and 7-fluorochrome multiplex fluorescence in situ hybridization, and we tried to show a relationship between gene expression patterns and chromosomal changes. These analyses revealed a number of genes involved in both the cell cycle and proliferation that are differently expressed in aged cells. More importantly, our data show an association between age-related aneuploidy and the gene expression level of genes involved in centromere and kinetochore function and in the microtubule and spindle assembly apparatus. To verify that some of these genes may also be involved in tumorigenesis, we compared the expression of these genes in chromosomally stable microsatellite instability and chromosomally unstable chromosomal instability colorectal tumor cell lines. Three genes (Notch2, H2AFY2, and CDC5L) showed similar expression differences between microsatellite instability and chromosomal instability cell lines as observed between the young and old cell cultures suggesting that they may play a role in tumorigenesis.
The lamins are major determinants of nuclear shape and chromatin organization and these features are frequently altered in prostate cancer (CaP). Human CaP cell lines frequently have nuclear lobulations, which are enriched in A-type lamins but lack B-type lamins and have been defined as lamin B-deficient microdomains (LDMDs). LDMD frequency is correlated with CaP cell line aggressiveness and increased cell motility. In addition, LNCaP cells grown in the presence of dihydrotestosterone (DHT) show an increased frequency of LDMDs. The LDMDs are enriched in activated RNA polymerase II (Pol IIo) and androgen receptor (AR) and A-type lamins form an enlarged meshwork that appears to co-align with chromatin fibres and AR. Furthermore, fluorescence in situ hybridization and comparative genomic hybridization demonstrated that chromosomal regions associated with CaP susceptibility are preferentially localized to LDMDs. Surprisingly, these regions lack histone marks for transcript elongation and exhibit reduced BrU incorporation, suggesting that Pol II is stalled within LDMDs. Real-time PCR of genes near androgen response elements (AREs) was used to compare transcription between cells containing LDMDs and controls. Genes preferentially localized to LDMDs showed significantly decreased expression, while genes in the main nuclear body were largely unaffected. Furthermore, LDMDs were observed in human CaP tissue and the frequency was correlated with increased Gleason grade. These results imply that lamins are involved in chromatin organization and Pol II transcription, and provide insights into the development and progression of CaP.
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