TRENDS in Biochemical Sciences Vol.26 No.1 January 2001 http://tibs.trends.com 0968-0004/01/$ – see front matter © 2001 Elsevier Science Ltd. All rights reserved. PII: S0968-0004(00)01727-8 41 Review Merav Cohen Yosef Gruenbaum* Dept of Genetics,The Institute of Life Sciences, The Hebrew University of Jerusalem, Jerusalem 91904, Israel. *e-mail: gru@vms.huji.ac.il Kenneth K. Lee Katherine L.Wilson Dept of Cell Biology and Anatomy,The Johns Hopkins University School of Medicine, 725 N. Wolfe St, Baltimore, M D 21205, USA. All authors contributed equally to the article. 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 (Fig. 1). Lamins are type V intermediate filament proteins. They range in size from 60 to 70 kDa and have a characteristic structure: a small N-terminal ‘head’, a 52-nm coiled-coil ‘rod’ and a globular C- terminal ‘tail’ 4 . Lamins form α-helical coiled-coil dimers, which are the building blocks for further assembly. In vitro, lamin dimers associate to form head-to-tail polymers. The assembly pathway and final structure(s) of lamin filaments are poorly understood. Indeed, lamin filaments are probably unlike the 10-nm diameter cytoplasmic intermediate filaments, because no 10-nm filaments have been detected in electron micrograph cross-sections, and the lamina isolated from Xenopus oocyte nuclei forms an orthogonal network rather than linear filaments 4 . There is strong evidence that lamins are not restricted to the nuclear periphery but exist throughout the nuclear interior 5 . It is not known if the peripheral and interior lamins form similar or different structures. However, given the growing number and types of lamin-binding proteins, some of these partners might influence the assembly or structural properties of lamins. The nuclear lamina provides structural support for chromosomes, and is required to maintain nuclear shape, space NPCs, replicate DNA and efficiently segregate chromosomes 2,3 . New functions for the lamina are discussed below. M etazoan evolution: a gradual increase in the complexity of nuclear lamina proteins Investigators are identifying a growing number of integral and peripheral membrane proteins that associate with lamins (Fig. 2). Hence, the term ‘nuclear lamina’ is general, and includes both lamins and lamin-binding proteins. Vertebrates have three lamin genes. The LMNA gene encodes four alternatively spliced A-type lamins named A, C, A ∆10 and C 2 . Two genes encode B-type lamins, LMNB1 (encoding lamin B1) and LMNB2 (encoding lamins B2 and B3) 4 . Several of these proteins are differentially expressed during development and differentiation, suggesting tissue-specific functions. In addition, vertebrates express many integral membrane proteins in the INM, including three isoforms of lamina-associated protein 1 (LAP1), at least five isoforms of LAP2, as well as emerin (mutations in which cause Emery–Dreifuss muscular dystrophy; EDMD), MAN1, lamin B receptor (LBR), nurim and probably UNC-84. A sixth isoform of LAP2, named LAP2α, lacks a transmembrane domain and is found throughout the nuclear interior during interphase. The L AP2 isoforms plus e merin and M AN1 are members of a family defined by a 43-residue ‘LEM’ domain near their N terminus 6 . There are two lamin genes in Drosophila (lamin Dm 0 and lamin C), and one in Caenorhabditis elegans (Ref. 4). The number of lamins expressed in each organism fits a pattern in which more complex eukaryotes have greater lamin diversity. Eukaryotes are defined as more complex if they have more cells and more distinct cell types, tissues and organs. Thus, adult hermaphrodite C. elegans 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. Transcriptional repression, apoptosis, human disease and the functional evolution of the nuclear lamina Merav Cohen, Kenneth K. Lee, Katherine L.Wilson and Yosef Gruenbaum