Lamins are nuclear intermediate filaments. In addition to their structural roles, they are implicated in basic nuclear functions such as chromatin organization, DNA replication, transcription, DNA repair, and cell-cycle progression. Mutations in human LMNAgene cause several diseases termed laminopathies. One of the laminopathic diseases is Hutchinson–Gilford progeria syndrome (HGPS), which is caused by a spontaneous mutation and characterized by premature aging. HGPS phenotypes share certain similarities with several apparently comparable medical conditions, such as aging and atherosclerosis, with the conspicuous absence of neuronal degeneration and cancer rarity during the short lifespan of the patients. Cell lines from HGPS patients are characterized by multiple nuclear defects, which include abnormal morphology, altered histone modification patterns, and increased DNA damage. These cell lines provide insight into the molecular pathways including senescence that require lamins A and B1. Here, we review recent data on HGPS phenotypes through the lens of transcriptional deregulation caused by lack of functional lamin A, progerin accumulation, and lamin B1 silencing.
Humans express four major lamin proteins: lamin B1 (LB1), lamin B2 (LB2), and lamins A and C (LA, LC), encoded by LMNB1, LMNB2, and LMNA genes, respectively. Lamins A, LB1, and LB2 are expressed as prelamins that contain a carboxyl-terminal CaaX motif. The cysteine in the CaaX motif undergoes farnesylation, followed by cleavage of the last three amino acids (aaX) and methyl esterification. While LB1 and LB2 remain farnesylated, LA undergoes additional cleavage of the last 15 amino acids and becomes nonfarnesylated.
The most frequent mutation in Hutchinson–Gilford progeria syndrome (HGPS), affecting approximately 90% of patients, is a de novo autosomal dominant, single base substitution mutation in LMNA (C1824T). This mutation activates a cryptic splice site, which produces a mutant LA protein with an internal deletion of 50 amino acids that disrupts the last cleavage step of prelamin A. This truncated LA, termed progerin, is permanently farnesylated, toxic to cells and displays altered structural and biochemical properties (De Sandre-Giovannoli et al., 2003; Eriksson et al., 2003). While LA is present both at the nuclear periphery and at nuclear interior, progerin localizes predominantly at the nuclear periphery (Capell et al., 2005; Glynn & Glover, 2005). Progerin expression leads to reduction in the protein levels of lamin B1, thus further disrupting the nuclear lamina (Capell et al., 2005; Scaffidi & Misteli, 2005; Taimen et al., 2009; Shimi et al., 2011)
In HGPS patients, progerin affects mostly tissues of mesenchymal origin, including bone, skin, fat, teeth, hair, and blood vessels, while mortality is primarily due to accelerated atherosclerosis. The most prominent HGPS cellular phenotypes are nuclear lobulation, heterochromatin alterations, mitochondrial dysfunction, and chromosomal and telomeres aberrations. Altered nuclear functions include compromised cell-cycle regulation, impaired DNA repair, increased apoptosis and senescence (Merideth et al., 2008; Burtner & Kennedy, 2010; Mehta et al., 2011; Trigueros-Motos et al., 2011; Fig. 1) The molecular mechanisms by which progerin causes tissue-specific effects, and the reasons for the similarities or differences between HGPS phenotypes and those of aging are largely obscure. Noteworthy, the cryptic splice site activated in HGPS to create progerin is also used at low frequency in healthy individuals. Increased progerin levels are found in cells with physiological aging (Scaffidi & Misteli, 2006; McClintock et al., 2007; Olive et al., 2010). Furthermore, reduced lamin B1 protein expression is also observed in human cells undergoing senescence where the loss of LB1 probably leads to activation of either p53 or pRb pathways and has been proposed to serve as a senescence-associated biomarker (Shimi et al., 2011; Freund et al., 2012).
General mechanisms of lamin-regulated gene expression
Gene expression is dependent on chromatin–nuclear lamina interactions, miRNA regulation, sequestration of specific transcription factors (TFs), and interactions with RNA polymerase II (pol II) transcription machinery (Gruenbaum et al., 2003; Malhas & Vaux, 2009; Fiserova & Goldberg, 2010; Mattout et al., 2011; Zwerger et al., 2011; Jung et al., 2012).
Although there are few examples for lamin-dependent gene activation (e.g., NF-ĸB and TonEBP/NFAT5 transcription pathways), generally lamins and lamin-associated proteins provide a repressive chromatin environment due to specific protein–chromatin interactions (Lammerding et al., 2004; Favale et al., 2007; Peric-Hupkes & van Steensel, 2010; Puckelwartz et al., 2011). The specific lamin-based complexes control binding to and release of lamin-associated proteins from the nuclear periphery, including emerin, MAN1, LAP2, LBR, SUN-1, and others (Wilson & Foisner, 2010). These lamin-based complexes probably regulate gene silencing and activation of developmentally regulated genes. (Nili et al., 2001; Somech et al., 2005; Holaska & Wilson, 2006; Meister et al., 2010; Bank & Gruenbaum, 2011; Mattout et al., 2011).
The nuclear lamina association with specific gene regulatory sequences requires the transcriptional repressor cKrox in a complex with histone deacetylase 3 and Lap2β, as well as methylation of histone 3 on lysine 9 (H3K9) (Towbin et al., 2012; Zullo et al., 2012). Mutations in lamins perturb lamin–chromatin interactions, spatial arrangement of chromosome territories and intranuclear chromosome folding (Scaffidi & Misteli, 2005; Mewborn et al., 2010; Mattout et al., 2011; Mehta et al., 2011; Puckelwartz et al., 2011; van Steensel, 2011).
Lamins provide a protein scaffold for the organization of TFs. The disruption of the nuclear lamina, especially that of LB1, affects DNA replication and leads to a significant reduction in pol II activity (Moir et al., 2000; Spann et al. 2002; Ljungman & Lane 2004; Shumaker et al. 2008: Musich & Zou, 2011). Lamins A interacts with several components of pol II transcription machinery, including nuclear actin, nuclear myosin 1, chromatin remodeling complexes, and ribonucleoproteins (Sasseville & Langelier, 1998; Bengtsson & Wilson, 2004; Columbaro et al., 2005; Simon et al., 2010; Euskirchen et al., 2011). The reduction in LB1 levels, the reduction of intracellular TATA-binding protein levels, and the diminished global transcription in progerin-expressing fibroblasts all provide important insights into the role of lamins in transcriptional regulation (Candelario et al., 2011).
Lamin A and actin
Actin polymers and nuclear myosin play a key role in transcription regulation by affecting chromatin remodeling and movement, as well as by forming complexes that facilitate progress of the transcription machinery along the DNA template (Visa & Percipalle, 2010). In vitro binding between lamin and actin, and actin polymerization assays mapped two actin-binding sites in the LA tail domain (Simon et al., 2010; Simon & Wilson, 2011). The in vitro study showed significant reduction in LA-actin binding and consequently, in LA-induced actin bundling in various diseases resulting from mutations in the C-tail domain of LA, including the HGPS deletion. Hence, it is possible that lamins, and in particular LA, regulate transcription by directly affecting actin polymerization.
Lamin and progerin interactions with miRNA
miRNAs are small RNA molecules that are involved in post-transcriptional regulation by binding to target mRNAs, usually resulting in translational repression and gene silencing. LMNA and LMNB1 expression is regulated by specific miRNAs. For example, miR-23 down-regulates LMNB1 (Lin & Fu, 2009) and the brain-specific miR-9 down-regulates LA and progerin, but not lamin C and might thus bear relevance to the absence of primary central nervous system involvement in HGPS (Jung et al., 2012). Lamins can regulate the expression of specific miRNAs. For example, LB1 binds and sequesters Oct1 (Malhas & Vaux, 2009). Insufficient LB1 yields unsequestered active Oct1, which leads to excess production of mir-31. In turn, mir-31 binds and silences p16(Ink4a)/p14(Arf) mRNA which normally inhibit progress through the cell cycle by maintaining the pRb checkpoint (p16/Ink4a) and augmenting p53 levels and function (p14/Arf) (Malhas et al., 2010). LB1 reduction in HGPS cells and over-activation of mir-31 might thus explain, at least in part, the initial phase of hyperproliferation that characterizes HGPF fibroblasts prior to their apoptotic death (Bridger & Kill, 2004).
Lamins, HGPS, and mechanotransduction
Mechanotransduction describes a mechanism by which cells adjust to changes in the mechanical load exerted by their environment in part by activating specific gene expression programs. The mechanotransduction properties of cells require lamins and emerin function and are probably mediated through LINC complexes that link the nuclear lamina with the actin cytoskeleton and the NF-kB transcription pathway (Starr, 2007; Zwerger et al., 2011). Lamin A-deficient cells have decreased nuclear stiffness and increased nuclear fragility (Broers et al., 2004; Lammerding et al., 2004). In response to mechanical stress, these cells display defective mechanotransduction and attenuated NFkB response, with impaired induction of mechano-sensitive and anti-apoptotic genes (Lammerding et al., 2004, 2005; Lammerding & Lee, 2005). Hutchinson-Gilford progeria syndrome fibroblasts, which are characterized by stiffer and less compliant nuclei, are also more sensitive to mechanical strain and react with cell apoptosis/necrosis and impaired strain-induced proliferation response (Lammerding et al., 2004; Dahl et al., 2006; Verstraeten et al., 2008).
In the vascular tree, HGPS cells fail to cope with fluid shear stress and thus contributing to vascular smooth muscle cells (VSMCs) loss and atherosclerosis (Verstraeten et al., 2008; Olive et al., 2010). The increased stiffness of HGPS fibroblasts suggests an increase in mechanical sensitivity and aberrant mechanotransduction of the progerin-expressing cells, including cells of the arterial walls. Notably, evaluation of NFkB in HGPS cells has not been reported yet. Deposition of progerin in the arterial walls might render HGPS cells more sensitive to mechanical strain and contribute to the aberrant mechanotransduction (Olive et al., 2010; Zwerger et al., 2011)
Lamin-regulated transcription mechanisms are altered in HGPS
The normal transcription pattern, particularly of genes encoding TFs, is altered in HGPS cells as indicated by genome-wide expression studies. (Csoka et al., 2004; Scaffidi & Misteli, 2008; Hernandez et al., 2010; Marji et al., 2010; Plasilova et al., 2011). In the next section, we discuss specific mechanisms by which lamins regulate and progerin deregulates gene expression in HGPS cells.
Chromatin organization and modifications
Several studies support LA involvement in higher order chromatin organization and anchorage, heterochromatin formation, histone modifications, and transcriptional activity (Dechat et al., 2010; Gonzalez-Suarez & Gonzalo, 2010). The critical role of LA in chromatin organization is evident by the properties of progerin-containing HGPS nuclei that show loss of peripheral heterochromatin and specific changes in chromatin-modifying enzymes such as decreased H3 Lys 27 methyltransferase (EZH2), decrease in the chromatin modifications H3K27m3, H3K9m3, and increased in H4K20m3 (Scaffidi & Misteli, 2006; Shumaker et al., 2006; Shimi et al., 2011). These epigenetic changes affect chromatin organization, transcription, senescence, and DNA repair. Interestingly, the specific profile of HGPS-associated histone modifications oppose those which have been found in several tumors and may thus explain in part the divergent HGPS phenotypes of premature aging and cancer rarity (Dimauro & David, 2009; Chi et al., 2010).
Telomere integrity is essential for maintaining chromosomes integrity and is therefore a key determinant of aging, cancer, and the viability of stem cells (Blasco, 2005). Telomere dysfunction results in genomic instability, activation of DNA damage responses (DDR), mitochondrial dysfunction, and stem cell exhaustion, which have all been implicated in the aging process (Sahin & Depinho, 2010). Interestingly, recent studies suggest possible interconnections between these aging effectors, thus linking DNA damage and metabolic pathways through a proposed ‘telomere - p53 – mitochondrial’ axis. Dysfunctional telomeres, recognized as DNA damage, activate p53, promote senescence, and compromises mitochondrial function due to PGC1 repression. Mitochondrial dysfunction, in turn, further aggravates functional decline of tissue stem cells and telomere dysfunction, thus setting up a vicious circle. The essential role of short telomeres in premature aging and the suggested telomere–mitochondrion link are demonstrated by Werner syndrome, which encompasses premature aging and a concomitant metabolic disorder of insulin-resistant diabetes (Sahin & Depinho 2012).
Loss of LA expression as well as increased expression of progerin cause gross telomere abnormalities, including telomere attrition and mislocalization. This phenotype is normally observed in cells undergoing senescence including HGPS fibroblasts (Raz et al., 2008; Gonzalez-Suarez et al., 2009; Benson et al., 2010). Intriguingly, a recent report pointed to a synergistic relationship between progerin production and telomere dysfunction during the induction of cellular senescence in normal human fibroblasts; The progressive telomere damage during cellular senescence plays a causative role in activating progerin production, while expression of progerin causes telomere shortening (Cao et al., 2011). This finding lends insight into the process of normal aging in which progerin levels are increased (Scaffidi & Misteli, 2006; McClintock et al., 2007; Olive et al., 2010). The progerin-induced telomere dysfunction activates DDR and p53-signaling pathways leading to senescence (Benson et al., 2010). In HGPS, the induction of senescence by DDR and p53 might substantially reduce stem cell populations and contribute to premature aging (Gotzmann & Foisner, 2006; Halaschek-Wiener & Brooks-Wilson, 2007). Activation of p53 in HGPS also augments mitochondrial dysfunction and stem cells exhaustion in part by repressing the mitochondrial PGC1 protein (Halaschek-Wiener & Brooks-Wilson, 2007; Sahin & Depinho, 2010; Sahin et al., 2011). Given that telomere attrition and dysfunction and mitochondrial dysfunction are both associated with cardiovascular disease (CVD) and atherosclerosis, they might also be implicated in HGPS-related atherosclerotic CVD (Calado & Young, 2009; Puddu et al., 2009; Viteri et al., 2010). Moreover, in the presence of activated p53, short telomeres suppress tumorigenesis, despite genomic instability, thus potentially contributing to cancer rarity in HGPS (Blasco, 2005).
Lamins A interacts with the nucleosome remodeling and deacetylation (NuRD) complex through association with RBBP4/7. Site of interaction is localized at the LA region (amino acids 562–664) that overlaps the region deleted in progerin. This interaction is crucial to form and maintain heterochromatin foci, H3K9 methylation and heterochromatin protein 1 gamma (HP1γ) chromatin association (Meshorer & Gruenbaum, 2009; Pegoraro et al., 2009). Indeed, silencing of individual NuRD subunits in normal cells recapitulated aging-associated chromatin defects, including heterochromatin loss. The inability of progerin to bind RBBP4/7 is likely responsible for the reduction in several NuRD proteins and the loss of peripheral heterochromatin in HGPS cells (Meshorer & Gruenbaum, 2009; Pegoraro et al., 2009).
LINC complexes in HGPS
Besides the impaired role of the LINC complexes in mechanotransduction, LA binding to the nuclear membrane SUN1 protein plays a key role in the etiology of HGPS (Crisp et al., 2006; Haque et al., 2006, 2010). Hutchinson-Gilford progeria syndrome cells display increased SUN1 levels at the nuclear envelope as SUN1 preferentially interacts with prelamin A/progerin (Goldman et al., 2004; Haque et al., 2010; Chen et al., 2012). Down-regulation of SUN1 by RNAi in HGPS cells restores nuclear shape, prevents the heterochromatin loss, and inhibits senescence (Chen et al., 2012).
Barrier-to-autointegration factor in HGPS
The distinct effects of LA on peripheral heterochromatin organization are further exemplified by LA interactions with the barrier-to-autointegration factor (BAF). Barrier-to-autointegration factor is involved in tethering heterochromatin to the nuclear envelope via its interactions with DNA, histones, RBBP4, LA, and LEM-domain proteins (Shumaker et al., 2001; Montes de Oca et al., 2009). Notably, the 50-amino acids deletion that characterizes progerin does not interfere with progerin-BAF binding. Binding of BAF to progerin as well as to LA and prelamin A result in loss of BAF cytoplasmic pool, and in its partial dysfunction probably due to loss of BAF interactions with the chromatin-organizing protein RBBP4 (Capanni et al., 2010). Interestingly, a recessive mutation in BAF causes segmental premature-aging syndrome that resembles HGPS but lacks atherosclerosis (Puente et al., 2011).
Altered regulation of specific transcription factors in HGPS
The interactions between lamins and various TFs–regulate tissue-specific transcriptional programs and lead in most cases to transcriptional repression (Mattout-Drubezki & Gruenbaum, 2003). The interactions operate through specific protein–protein interactions, via sequestration of TFs to the nuclear periphery and by affecting nuclear pore complexes (NPCs) positioning and function (Heessen & Fornerod, 2007; Andrés & González, 2009; Marmiroli et al., 2009; Fiserova & Goldberg, 2010). A summary of TFs that are regulated directly or indirectly by lamin A/progerin and their relevance to HGPS pathology is shown in Table 1. PRX1 (Kubben et al., 2010), MEOX/GAX (Csoka et al., 2004), and TWIST2 (Plasilova et al., 2011) appear only in Table 1. Moreover, progerin expression disrupts the Ran gradient and reduces the function of the SUMOylation pathway (Kelley et al., 2011). These effects might contribute to the compromised nucleo-cytoplasmic transport of TFs through the NPC. Furthermore, SUMO pathway disruption might also compromise the regulation of lamin A by SUMO2 (Zhang & Sarge, 2008), SUMO3 (Galisson et al., 2011), and SUMO1 (Simon et al., 2013). Interestingly, Farnesyl transferase inhibitor (FTIs) treatment has been found to prevent progerin effects on the Ran-GTPase system, a fact that might further expand FTIs therapeutic yield (Kelley et al., 2011).
Table 1. Possible effects of lamins/progerin-related transcription factors on HGPS phenotypes
Altered response to mechanical strain (in LA-deficient cells)
Increased apoptosis /necrosis
Vasculopathy, CVD, atherosclerosis
Altered LEF1 localization & activity
Stem cells exhaustion
Mesenchymal stem cells dys:
Lipodystrophy bone abnormalities
Preferential progerin binding
Down-regulated interaction with Tenascin-C
See above: in Wnt
Vasculopathy, CVD, atherosclerosis
Vasculopathy, CVD, atherosclerosis
The retinoblastoma tumor suppressor (pRb) protein regulates numerous TFs and determines cell-fate and differentiation (Burkhart & Sage, 2008). Lamins A and its associated protein LAP2α interact with the pRb, as well as with inhibitor-of-growth-protein1 (ING1). These interactions probably regulate pRb association with HP1, histones, and chromatin remodeling enzymes and contribute to chromatin recruitment to the nuclear periphery (Gonzalo & Blasco, 2005). Genome-wide expression studies identified the LA-pRb-signaling network as a major pathway affected in HGPS (Marji et al., 2010). Indeed, loss of LA activity leads to mislocalization, increased proteasomal degradation and inactivation of pRb (Johnson et al., 2004; Nitta et al., 2007; Andrés & González, 2009; Boban et al., 2010).
Binding of LA and LAP2α to pRb probably modulates TGFβ effects on fibroblasts proliferation. Moreover, LA inhibits TGFβ-induced fibroblast proliferation by its effects on PP2A, which promotes pRb and Smads 2/3 dephosphorylation (Van Berlo et al., 2005). Lamins A also associates with MAN1 (Mansharamani & Wilson, 2005), which also regulates Smads phosphorylation and sequestration (Lin et al., 2005; Pan et al., 2005; Van Berlo et al., 2005; Ishimura et al., 2006; Cohen et al., 2007). Disruption of these interactions might lead to uncontrolled fibroblasts proliferation and fibrosis, thus contributing to HGPS-related sclerotic skin abnormalities and atherosclerotic CVD (Blobe et al., 2000; Merideth et al., 2008). Notably, the prominent adventitial fibrosis is a major characteristic of the ‘atypical’ HGPS atherosclerotic CVD along with primary loss of medial VSMCs, deposition of progerin and changes in the composition of the extracellular matrix (Merideth et al., 2008; Olive et al., 2010).
pRb also affects osteogenesis and bone development by binding and potentiating Runx2, which is involved in the development and maintenance of bone and cartilage (Thomas et al., 2001). Lamins A silencing impairs osteoblastogenesis indicating that it is critical for bone development (Akter et al., 2009; Rauner et al., 2009). Nevertheless, direct LA–Runx2 interaction has not been documented
Aberrant interaction of progerin with TFs can also account for impaired adipogenesis normally controlled by the SREBP1- and PPARγ transcriptional pathways (Capanni et al., 2005; Siersbaek et al., 2010; Duband-Goulet et al., 2011). Nevertheless, SREBP1 binds with high affinity to prelamin A, as well as to progerin resulting in SREBP1 sequestration at the nuclear envelope with concomitant reduction in its intranuclear availability and thus in reduced transcriptional activity of its target genes. In addition, PPARγ is down-regulated and adipocyte differentiation is inhibited in cultured pre-adipocytes (Capanni et al., 2005; Maraldi et al., 2008). As PPARγ also has anti-inflammatory and anti-atherosclerotic activities (Takano & Komuro, 2009), its suppression might enhance CVD in HGPS patients.
The inhibitor-of-growth-protein1 (ING1) is a member of the ING family of proteins. The ING proteins play a key role in cell-cycle progression, apoptosis, cell aging, and DDR. Inhibitor-of-growth-protein1 functions in the nucleus as an epigenetic regulator by binding to epigenetic determinants mostly on histone H3 and to either histone acetylase or deacetylase complexes (Soliman & Riabowol, 2007). Inhibitor-of-growth-protein1 binds to the N-terminal region of LA rod domain (amino acids 1–406) (Han et al., 2008). The inability of progerin to bind ING1 at physiological levels suggests that the tail region of lamins profoundly affects the ability of the rod domain to interact with ING1. Lamins A association stabilizes ING1 and targets it to the nucleus (Han et al., 2008). In cells, where ING1-LA association is abrogated, ING1 protein levels are markedly reduced, and it is aberrantly sequestered in the cytoplasm. Re-expression of LA in LA-null cells restored ING1 expression and nuclear localization (Han et al., 2008). A model has been proposed according to which tethering by LA has a dual function: it stabilizes ING1 as well as spatially regulates its epigenetic activity (Soliman & Riabowol, 2007; Han et al., 2008). The reduced ING1-LA association in HGPS cells can help to explain the loss of peripheral chromatin in these cells. Nevertheless, the precise role of LA-ING1 association in cellular senescence, heterochromatin formation, and its linkage to different HGPS phenotypes remains largely unknown.
Altered regulation of adult stem cells in HGPS
Recent studies suggest that aberrant regulation of adult stem cell likely affects premature aging in HGPS. Lamins A associates with the Notch co-activator SKIP, regulates SKIP availability and Notch transcriptional activity (Scaffidi & Misteli, 2008). Progerin has a reduced affinity to SKIP leading to an increase in its intranuclear availability and activation of downstream effectors of Notch, which in turn alter the differentiation pathways of mesenchymal stem cells. Indeed, Notch pathway components are markedly overexpressed in several mesenchymal cell line isolated from HGPS patients, while progerin interference with the Notch signaling pathway inhibits mesenchymal stem cell differentiation (Scaffidi & Misteli, 2008). The aberrant regulation of the Notch signaling pathway could account for the phenotypes of mesoderm-derived adipose, bone, and vascular smooth muscle tissues in HGPS (Rosen & MacDougald, 2006; Gridley, 2007; Canalis, 2008; Kurpinski et al., 2010; Andersson et al., 2011).
The Wnt/β-catenin pathway regulates mesenchymal stem cell proliferation and differentiation with specific roles in skeleton and cartilage development (Day et al., 2005; Chen et al., 2008). In a mouse progeria model, the extracellular matrix (ECM) of adult mice is defective and does not support fibroblasts cell proliferation. The resulting cell senescence is due to the reduced nuclear localization and transcriptional activity of the Wnt-signaling target Lef1, a phenomenon that is also observed in fibroblasts derived from HGPS patients (Hernandez et al., 2010). Microarray studies on HGPS fibroblasts and mesenchymal stem cells confirm profound misregulation of ECM genes expression (Csoka et al., 2004; Scaffidi & Misteli, 2008; Zhang et al. 2011). The gene expression alterations in HGPS fibroblasts suggest excess of ECM deposition, resulting from increased expression of ECM components and decreased expression of ECM-remodeling enzymes (Csoka et al., 2004). These findings support the hypothesis that defective ECM triggers the skeletal, dental, skin, and vascular abnormalities in HGPS (Csoka et al., 2004; Hernandez et al., 2010). Importantly, since inappropriate activation of the Wnt pathway has been related to cancer (Klaus & Birchmeier, 2008), its down-regulation in HGPS might contribute to cancer rarity despite accelerated aging.
Compromised DNA damage repair in HGPS cells
Hutchinson-Gilford progeria syndrome cells accumulate DNA double-strand breaks (DSBs) and show a compromised DDR attributed mainly to progerin expression, lack of functional LA, and ROS accumulation (Musich & Zou, 2011; Richards et al., 2011). The LA roles in chromatin organization and its interactions with histone H2A, emerin, ING1, and PCNA as described previously help explain its involvement in the DDR (Mattout-Drubezki & Gruenbaum, 2003; Shumaker et al., 2006; Han et al., 2008).
It has been shown that in LA-null cells, the loss of LA induces transcriptional up-regulation of the cysteine protease Cathepsin L (CTSL). This observation suggests a direct or indirect repression of CTSL by LA (Gonzalez-Suarez et al., 2011). In addition, up-regulation of CTSL was also reported in mouse model of progeria (Varela et al., 2008). By mediating transcriptional regulation of the CTSL, LA directly regulates the levels of major nonhomologous end joining and homologous recombination repair proteins such as 53BP1 and the p130/E2F4 repressor complexes, which in turn, regulate the transcription of the DNA repair proteins RAD51 and BRCA1 (Gonzalez-Suarez et al., 2011; Redwood et al., 2011). Notably, LA also stabilizes 53BP1 by preventing its proteolysis (Gonzalez-Suarez et al., 2009). Indeed, cell lines that express progerin or lack LA activity display impaired DDR pathways (Liu et al., 2005; Manju et al., 2006; Gonzalez-Suarez et al., 2011; Redwood et al., 2011). Progerin further enhances DSBs accumulation and impaired DDR by its aberrant interaction with PCNA and lack of interaction with ING1, which leads to peripheral sequestration of several replication and DNA repair factors and stalled replication forks that collapse into DSBs (Musich & Zou, 2009, 2011). In addition, the progerin-mediated loss of various NuRD subunits further compromises the DDR by perturbing NuRD roles in recruitment of DNA repair proteins, and in promoting transcriptional repression, which facilitates the repair process (Lai & Wade, 2011). In conclusion, progerin-mediated DNA damage accumulation and compromised DDR bear direct relevance to HGPS-related premature aging and deregulated transcription. Additionally, as DDR goes awry, the resultant persistent damage signaling activates p53, thus promoting senescence and tumor suppression (Collado et al., 2007).
Cancer in HGPS
Hutchinson–Gilford progeria syndrome is characterized by cancer rarity (Hennekam, 2006; Burtner & Kennedy, 2010). It is possible that cancer predisposition is masked by the short lifespan of the patients. Nevertheless, a unique constellation of several factors might explain the divergent HGPS phenotypes of premature aging and cancer rarity.
The potential pro-cancerous effects of DNA damage accumulation and compromised DNA repair might be counteracted by the HGPS-associated p53 activation, short telomeres, and the specific profile of histone modifications (Ljungman & Lane 2004; Campisi & d'Adda di Fagagna, 2007). Interestingly, the two cases of cancer reported thus far in HGPS patients refer to osteosarcoma (King et al., 1978; Shalev et al., 2007), which is known, in its genetic as well as its sporadic occurrence, to be related mainly to p53 or pRb dysfunction (Lerner & Antman, 2012).
The data reviewed hereby support the concept that the lamins-associated transcriptional regulation in HGPS cells is impaired and can explain major HGPS phenotypes (Fig. 2). Additionally, it may explain the absence of primary neuronal degeneration, the rarity of cancer, and the various differences from atherosclerotic CVD. The proposed concept integrates suitably with current molecular aging theories (Blagosklonny et al., 2010) and indicates a pivotal role for p53 in HGPS as it promotes senescence/aging, suppresses tumorigenesis and activates autophagy through its negative regulation of the mTOR pathway.
Transcriptional deregulation in HGPS appears to be closely related to lack of normal functional LA, LB1 silencing, and disruption of lamins network integrity. It seems to play a major role in HGPS pathogenesis, adding thus to progerin insults. Moreover, in addition to current therapies, aimed to eliminate progerin and inhibit its farnesylation, there might be a place for therapeutic interventions addressing specific alterations in TFs-controlled pathways and their downstream effects. Such potential therapeutic agents include rapamycin (inhibits mTORC1 pathway), tyrosine-kinase inhibitors (block fibrosis via TGFβ signaling), statins (activate PPARγ), and ROS scavengers (decrease levels of unrepaired DSBs which interfere with transcription).
The famous saying ‘inside every old person is a young person wondering what happened’ is tragically true in HGPS in view of the speedy progression of devastating aging-phenotypes and fatal outcome. Identifying NL-associated transcriptional deregulation as a possible molecular mechanism underlying HGPS phenotypes might help understand some of the disease's mysteries, and offer an intriguing concept for future research.
We thank Yuval Reiss, Eran Meshorer, Michal Goldberg and members of the Gruenbaum laboratory for their comments on the manuscript. We gratefully acknowledge funding from the Morasha Legacy 1798/10, Israel Ministry of Health (MOH 2965), the Muscular Dystrophy Association (MDA), the Israeli Science Foundation, the Binational Israel-USA Science Foundation (BSF 2007215) and the COST NANONET (BM1002).