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 premature aging disease Hutchinson-Gilford Progeria Syndrome (HGPS) is caused by a mutant lamin A (LA⌬50). Nuclei in cells expressing LA⌬50 are abnormally shaped and display a loss of heterochromatin. To determine the mechanisms responsible for the loss of heterochromatin, epigenetic marks regulating either facultative or constitutive heterochromatin were examined. In cells from a female HGPS patient, histone H3 trimethylated on lysine 27 (H3K27me3), a mark for facultative heterochromatin, is lost on the inactive X chromosome (Xi). The methyltransferase responsible for this mark, EZH2, is also down-regulated. These alterations are detectable before the changes in nuclear shape that are considered to be the pathological hallmarks of HGPS cells. The results also show a down-regulation of the pericentric constitutive heterochromatin mark, histone H3 trimethylated on lysine 9, and an altered association of this mark with heterochromatin protein 1␣ (Hp1␣) and the CREST antigen. This loss of constitutive heterochromatin is accompanied by an up-regulation of pericentric satellite III repeat transcripts. In contrast to these decreases in histone H3 methylation states, there is an increase in the trimethylation of histone H4K20, an epigenetic mark for constitutive heterochromatin. Expression of LA⌬50 in normal cells induces changes in histone methylation patterns similar to those seen in HGPS cells. The epigenetic changes described most likely represent molecular mechanisms responsible for the rapid progression of premature aging in HGPS patients.histone methylation ͉ heterochromatin ͉ progeria H utchinson-Gilford Progeria Syndrome (HGPS) is a premature aging disease usually diagnosed in the first 12-18 months of life (1). HGPS is characterized by a rapid progression of disorders including hair loss, growth retardation, lack of s.c. fat, aged-looking skin, osteoporosis, and arteriosclerosis (2, 3). Patients with HGPS usually die from heart attacks or strokes at Ϸ13 years (4). The common form of HGPS is caused by a conservative heterozygous mutation (1824 CϾT) in the human nuclear lamin A (LA) gene (LMNA), which introduces a splice site resulting in the synthesis of LA with 50 amino acids deleted near its C terminus [mutant LA (LA⌬50)] (5, 6).Nuclear lamins are divided into A and B types. Lamins A and C (LA͞C) are derived from LMNA by alternative splicing, whereas lamins B1 and B2 are derived from different genes. The B type lamins are expressed in every cell, whereas the expression of A type lamins is developmentally regulated. Lamins have a common tripartite structure with an ␣-helical central rod domain flanked by globular N-and C-terminal domains (7). The basic structural unit of lamins is a dimer consisting of two parallel and in-register protein chains that form a coiled coil through the association of their rod domains (8). Lamin dimers assemble in a head-to-tail fashion forming protofilaments that interact laterally to form numerous higher-order structures (9).Lamins are the major components of the nuclear lam...

The nuclear lamins are type V intermediate filament proteins that are critically important for the structural properties of the nucleus. In addition, they are involved in the regulation of numerous nuclear processes, including DNA replication, transcription and chromatin organization. The developmentally regulated expression of lamins suggests that they are involved in cellular differentiation. Their assembly dynamic properties throughout the cell cycle, particularly in mitosis, are influenced by posttranslational modifications. Lamins may regulate nuclear functions by direct interactions with chromatin and determining the spatial organization of chromosomes within the nuclear space. They may also regulate chromatin functions by interacting with factors that epigenetically modify the chromatin or directly regulate replication or transcription.

It took more than 100 years before it was established that the proteins that form intermediate filaments (IFs) comprise a unified protein family, the members of which are ubiquitous in virtually all differentiated cells and present both in the cytoplasm and in the nucleus. However, during the past 2 decades, knowledge regarding the functions of these structures has been expanding rapidly. Many disease-related roles of IFs have been revealed. In some cases, the molecular mechanisms underlying these diseases reflect disturbances in the functions traditionally assigned to IFs, i.e., maintenance of structural and mechanical integrity of cells and tissues. However, many disease conditions seem to link to the nonmechanical functions of IFs, many of which have been defined only in the past few years.

Mutations in the gene encoding nuclear lamin A (LA) cause the premature aging disease Hutchinson-Gilford Progeria Syndrome. The most common of these mutations results in the expression of a mutant LA, with a 50-aa deletion within its C terminus. In this study, we demonstrate that this deletion leads to a stable farnesylation and carboxymethylation of the mutant LA (LA⌬50/progerin). These modifications cause an abnormal association of LA⌬50/ progerin with membranes during mitosis, which delays the onset and progression of cytokinesis. Furthermore, we demonstrate that the targeting of nuclear envelope/lamina components into daughter cell nuclei in early G 1 is impaired in cells expressing LA⌬50/ progerin. The mutant LA also appears to be responsible for defects in the retinoblastoma protein-mediated transition into S-phase, most likely by inhibiting the hyperphosphorylation of retinoblastoma protein by cyclin D1/cdk4. These results provide insights into the mechanisms responsible for premature aging and also shed light on the role of lamins in the normal process of human aging.cell division ͉ nuclear lamins ͉ nuclear structure ͉ progeria ͉ protein farnesylation