Laminopathic mutations interfere with the assembly, localization, and dynamics of nuclear lamins

Wiesel, Naama; Mattout, Anna; Melcer, Shai; Melamed-Book, Naomi; Herrmann, Harald; Medalia, Ohad; Aebi, Ueli; Gruenbaum, Yosef

doi:10.1073/pnas.0708974105

Cited by 96 publications

(149 citation statements)

References 32 publications

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“…Although substituting lysine for glutamic acid at residue 145 does not alter dimer assembly as shown by AUC analysis, it does alter the normal alignment of protofilaments into filaments and PCs (2). In further support of this, a mutation in the corresponding site of Caenorhabditis elegans lamin (lmn-1), Q159K, alters the structure of in vitro assembled filaments (21,26).…”

Section: Discussionmentioning

confidence: 76%

A progeria mutation reveals functions for lamin A in nuclear assembly, architecture, and chromosome organization

Taimen

Pfleghaar²,

Shimi

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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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.

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Section: Discussionmentioning

confidence: 76%

A progeria mutation reveals functions for lamin A in nuclear assembly, architecture, and chromosome organization

Taimen

Pfleghaar²,

Shimi

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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195

215

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“…In an effort to understand the underlying mechanism of various laminopathies, a number of disease-related lamin mutations have been introduced into C. elegans. Many of these mutations disrupted C. elegans LMN-1 oligomerization in vitro and lamin function in vivo (Wiesel et al 2008;Bank et al 2011Bank et al , 2012Mattout et al 2011;Zuela et al 2016). For example, LMN-1DK46, which corresponds to the deletion of lysine 32 in the rod domain of lamin A/C in Emery-Dreifuss muscular dystrophy patients, causes defects in the lateral assembly of LMN-1 dimers and results in abnormal muscle structure and motility in the worm .…”

Section: Components Of the Nementioning

confidence: 99%

Cell Biology of theCaenorhabditis elegansNucleus

Cohen-Fix

Askjaer

2017

Genetics

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Studies on the Caenorhabditis elegans nucleus have provided fascinating insight to the organization and activities of eukaryotic cells. Being the organelle that holds the genetic blueprint of the cell, the nucleus is critical for basically every aspect of cell biology. The stereotypical development of C. elegans from a one cell-stage embryo to a fertile hermaphrodite with 959 somatic nuclei has allowed the identification of mutants with specific alterations in gene expression programs, nuclear morphology, or nuclear positioning. Moreover, the early C. elegans embryo is an excellent model to dissect the mitotic processes of nuclear disassembly and reformation with high spatiotemporal resolution. We review here several features of the C. elegans nucleus, including its composition, structure, and dynamics. We also discuss the spatial organization of chromatin and regulation of gene expression and how this depends on tight control of nucleocytoplasmic transport. Finally, the extensive connections of the nucleus with the cytoskeleton and their implications during development are described. Most processes of the C. elegans nucleus are evolutionarily conserved, highlighting the relevance of this powerful and versatile model organism to human biology.KEYWORDS Caenorhabditis elegans; chromatin; gene expression; lamin; LEM-domain proteins; LINC; P granule; nuclear pore complex; nuclear envelope; nucleocytoplasmic transport; nucleolus; WormBook TABLE OF CONTENTSAbstract 25 C. elegans as a model system to study cell biology of the nucleus 26 Structural components of the nucleus 27

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“…The tail domain of lamins contains an Ig fold fl anked by unstructured regions. Lamins form stable, fi brous structures both at the nuclear periphery and in the nucleoplasm ( Moir et al, 2000 ;Wiesel et al, 2008 ).Lamins are divided into A and B types based on their expression patterns and protein structure. A-type lamins are found only in more complex metazoans and are expressed in differentiSpecifi c mutations in the human gene encoding lamin A or in the lamin A -processing enzyme, Zmpste24, cause premature aging.…”

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confidence: 99%

Gone with the Wnt/Notch: stem cells in laminopathies, progeria, and aging

Meshorer¹,

Gruenbaum²

2008

J Exp Med

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Many premature aging diseases are caused by mutations in the lamin A gene, resulting in severe nuclear abnormalities, but, curiously, although some tissues show severe phenotypes, others are hardly affected. Two new studies, Scaffi di and Misteli (2008) and Espada et al. (see p. 27 of this issue), show that somatic stem cells are misregulated in premature aging, explaining some of the pathological defects observed in these situations. Structure and function of nuclear laminsThe nuclear lamina underlies the inner membrane of the nuclear envelope (inner nuclear membrane [INM]). It is composed of lamins and lamin-associated proteins, including integral proteins of the INM. Lamins interact directly or indirectly with many known INM proteins, several nucleoplasm proteins, and proteins that bridge the inner and outer nuclear membranes and interact with cytoskeleton elements. These lamin-based complexes are involved in most nuclear activities, including determining nuclear structure, spacing of nuclear pores, replication of DNA, regulation of gene expression, transcription by RNA Pol II, nuclear positioning, segregation of chromosomes, meiosis, and apoptosis ( Gruenbaum et al., 2005 ).Lamins are type V intermediate fi lament proteins. They are found in all metazoans, and, like all intermediate fi lament proteins, they are composed of a short globular N-terminal (head) domain, an ␣ -helical rod domain, and a globular C (tail) domain. The tail domain of lamins contains an Ig fold fl anked by unstructured regions. Lamins form stable, fi brous structures both at the nuclear periphery and in the nucleoplasm ( Moir et al., 2000 ;Wiesel et al., 2008 ).Lamins are divided into A and B types based on their expression patterns and protein structure. A-type lamins are found only in more complex metazoans and are expressed in differentiSpecifi c mutations in the human gene encoding lamin A or in the lamin A -processing enzyme, Zmpste24, cause premature aging. New data on mice and humans suggest that these mutations affect adult stem cells by interfering with the Notch and Wnt signaling pathways.

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Laminopathic mutations interfere with the assembly, localization, and dynamics of nuclear lamins

Cited by 96 publications

References 32 publications

A progeria mutation reveals functions for lamin A in nuclear assembly, architecture, and chromosome organization

A progeria mutation reveals functions for lamin A in nuclear assembly, architecture, and chromosome organization

Cell Biology of theCaenorhabditis elegansNucleus

Gone with the Wnt/Notch: stem cells in laminopathies, progeria, and aging

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