Nuclear lamins and chromatin: When structure meets function

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Introduction

The nucleus of eukaryotic cells can be sub-divided into three main compartments: chromatin, intranuclear non-membrane bound complexes (which more or less act like cytoplasmic “organelles”), and the nuclear envelope (NE) (Schneider and Grosschedl, 2007, Spector, 2006, Verstraeten et al., 2007). The NE is composed of the outer and inner nuclear membrane (INM), nuclear pore complexes (NPCs) and the nuclear lamina. The latter is a proteinaceous meshwork underlying the INM and is connected to NPCs (Aaronson and Blobel, 1975). There is also evidence for a structural meshwork inside the nucleus (Barboro et al., 2002, Hozak et al., 1995, Vlcek et al., 2001). This internal nucleoskeleton together with the peripheral lamina forms a scaffold which is involved in chromatin organization and the correct spatial and temporal progression of nuclear processes such as DNA replication and transcription (Bridger et al., 2007, Dechat et al., 2008, Dorner et al., 2007). Major components of this scaffold are the nuclear lamins (Shumaker et al., 2003). In this review we discuss recent findings supporting the role of lamins in the organization and regulation of chromatin.

Section snippets

An overview of the nuclear lamins

Nuclear lamins, type V intermediate filament proteins, are divided into A- and B-types based on their sequence homologies (Broers et al., 2006, Goldman et al., 2002, Shumaker et al., 2003). All A-type lamins are encoded by a single gene (LMNA). Their major isoforms are lamins A and C, which are derived by alternative splicing. The two major mammalian B-type lamins, lamins B1 and B2, are encoded by different genes (LMNB1 and LMNB2). At least one lamin isoform is present in every nucleated

Nuclear lamins and their association with chromatin

The organization of interphase chromosomes into specific compartments and territories within the nucleus of eukaryotic cells is essential for proper chromatin function (Dillon, 2008, Fraser and Bickmore, 2007, Kalverda et al., 2008, Lanctot et al., 2007, Misteli, 2007, Trinkle-Mulcahy and Lamond, 2008). There is increasing evidence that nuclear lamins play an important role in this organization. This evidence comes mainly from three experimental approaches: biochemical analyses of the

The role of lamins in gene regulation

The role of the nuclear lamina and of nuclear lamins in gene expression is highlighted in several recent reviews (see Bridger et al., 2007, Dechat et al., 2008, Dorner et al., 2007, Heessen and Fornerod, 2007, Shaklai et al., 2007, Verstraeten et al., 2007). Therefore we focus on the most recent studies. In general the nuclear lamina is considered as a transcriptionally inactive region. Initial evidence for the involvement of lamins in transcription comes from a dominant negative lamin mutant

Lamins in DNA replication

Lamin B is present at sites of BrdU incorporation and at replication foci containing the proliferating cell nuclear antigen (PCNA) in late S-phase of cultured cells suggesting a role for nuclear lamins in DNA replication (Moir et al., 1994). The functional significance of this finding is supported by additional experiments using the Xenopus egg interphase extract nuclear assembly system. For example, nuclei assembled in a lamin-depleted extract are unable to replicate their DNA (Meier et al.,

Summary

In our model we propose that lamins are major components of a nuclear scaffold which is essential for various nuclear processes such as transcription, DNA replication, chromatin organization and DNA repair (Dechat et al., 2008, Goldman et al., 2002). We further speculate that this lamin based scaffold provides a docking site and organizing center for chromatin and the multicomponent complexes involved in chromatin regulation. Alterations in such a scaffold caused either by changes in lamin

Acknowledgments

We wish to thank the NIA, NCI and the Ellison Medical Research Foundation for supporting our studies of the nuclear lamins.

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