Human progeroid syndromes, aging and cancer: new genetic and epigenetic insights into old questions

Ramírez, C. L.; Cadiñanos, Juan; Varela, Ignacio; Freije, José M.P.; López-Otı́n, Carlos

doi:10.1007/s00018-006-6349-3

Cited by 76 publications

(52 citation statements)

References 138 publications

(176 reference statements)

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“…In particular, the expression of A-type lamins mutant isoforms has been associated with defective DNA repair. 22,23 Our recent findings reveal that loss of A-type lamins impacts on the maintenance of telomeres and a proper DNA damage response.…”

Section: Introductionmentioning

confidence: 98%

Loss of A-type lamins and genomic instability

González-Suárez¹,

Redwood²,

Gonzalo³

2009

Cell Cycle

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Research performed in the last few years has revealed important roles for the spatial and temporal organization of the genome on genome function and integrity. A challenge in the field is to determine the molecular mechanisms involved in the organization of genome function. A-type lamins, key structural components of the nucleus, have been implicated in the maintenance of nuclear architecture and chromatin structure. Interestingly, alterations of A-type lamins lead to defects in DNA replication and repair as well as gene transcription and silencing. Elucidating the functions of these proteins is a topical subject since alterations of A-type lamins are associated with a variety of human diseases, ranging from muscular dystrophies and premature aging syndromes to cancer. Here, we discuss novels roles for A-type lamins in the maintenance of telomere structure, length and function as well as in the stabilization of a key DNA damage response factor. These studies support the notion that increased genomic instability due to defects in telomere biology and DNA repair contribute to the pathogenesis of lamin-related diseases.

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Section: Introductionmentioning

confidence: 98%

Loss of A-type lamins and genomic instability

González-Suárez¹,

Redwood²,

Gonzalo³

2009

Cell Cycle

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“…This final cleavage event is critically important for lamin A as several human disorders result from a lack of cleavage, including the premature aging disorder Hutchinson-Gilford Progeria Syndrome (HGPS) and the related progeroid disorders restrictive dermopathy (RD) and some forms of mandibuloacral dysplasia (MAD-B; Scaffidi et al, 2005;Capell and Collins, 2006;Ramirez et al, 2006;Young et al, 2006;Kudlow et al, 2007). It is notable that B-type lamins do not undergo endoproteolytic cleavage by Zmpste24 and retain their CaaX modifications, whereas lamin C (a splice variant of the lamin A/C gene) lacks a CaaX motif and is not modified at all.…”

Section: Introductionmentioning

confidence: 99%

Analysis of Prelamin A Biogenesis Reveals the Nucleus to be a CaaX Processing Compartment

Barrowman¹,

Hamblet²,

George³

et al. 2008

MBoC

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Proteins establish and maintain a distinct intracellular localization by means of targeting, retention, and retrieval signals, ensuring most proteins reside predominantly in one cellular location. The enzymes involved in the maturation of lamin A present a challenge to this paradigm. Lamin A is first synthesized as a 74-kDa precursor, prelamin A, with a C-terminal CaaX motif and undergoes a series of posttranslational modifications including CaaX processing (farnesylation, aaX cleavage and carboxylmethylation), followed by endoproteolytic cleavage by Zmpste24. Failure to cleave prelamin A results in progeria and related premature aging disorders. Evidence suggests prelamin A is imported directly into the nucleus where it is processed. Paradoxically, the processing enzymes have been shown to reside in the cytosol (farnesyltransferase), or are ER membrane proteins (Zmpste24, Rce1, and Icmt) with their active sites facing the cytosol. Here we have reexamined the cellular site of prelamin A processing, and show that the mammalian and yeast processing enzymes Zmpste24 and Icmt exhibit a dual localization to the inner nuclear membrane, as well as the ER membrane. Our findings reveal the nucleus to be a physiologically relevant location for CaaX processing, and provide insight into the biology of a protein at the center of devastating progeroid diseases. INTRODUCTIONThe nuclear envelope consists of an inner and outer membrane. The outer nuclear membrane (ONM) is continuous with the endoplasmic reticulum (ER) and connects with the inner nuclear membrane (INM) at the nuclear pore membrane (POM; Lusk et al., 2007). Integral membrane proteins that reside in the INM are initially inserted into the endoplasmic reticulum (ER) membrane and move via the POM to the INM where they maintain a concentrated localization by binding to chromatin or tethering to the nuclear lamina (Powell and Burke, 1990;Soullam and Worman, 1993;Holmer and Worman, 2001;Ohba et al., 2004;Lusk et al., 2007;Schirmer and Foisner, 2007). Until recently, conventional wisdom held that the localization of proteins to either the ER membrane or the INM is mutually exclusive. For example, proteins that are found within the INM, such as LAP1, are not generally found throughout the ER/ONM; likewise, ER proteins such as HMG-CoA reductase are strictly localized to the ER (Wright et al., 1988;Powell and Burke, 1990;Deng and Hochstrasser, 2006). It was recently shown that a notable exception to this paradigm is the yeast E3 ubiquitin ligase, Doa10p. Doa10p was long known to reside in the ER membrane (Swanson et al., 2001;Kreft et al., 2006). However, recent data indicate that Doa10p exhibits dual steady-state localizations, residing and functioning in both the ER membrane where it mediates ER-associated degradation of membrane and secretory proteins, and in the INM where it mediates degradation of the nuclear transcription factor MAT␣2 (Deng and Hochstrasser, 2006).The present study documents another exception to the mutual exclusivity of ER membrane and INM localizati...

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“…Over the last few years, our knowledge of the molecular basis of aging has gained mechanistic insight from studies on progeroid syndromes in which features of human aging are manifested precociously or in an exacerbated form. The vast majority of progeroid syndromes are a consequence of inefficient DNA repair mechanisms or defective nuclear envelope assembly, which ultimately lead to DNA damage accumulation and chromosome instability (3). Thus, mutations in the gene encoding lamin A (an essential component of the nuclear envelope) or in Zmpste24 (encoding a metalloproteinase involved in the maturation of lamin A) are responsible for several devastating human progeroid syndromes, including Hutchinson-Gilford progeria, atypical Werner syndrome, restrictive dermopathy, and mandibuloacral dysplasia (3)(4)(5)(6)(7).…”

mentioning

confidence: 99%

“…The vast majority of progeroid syndromes are a consequence of inefficient DNA repair mechanisms or defective nuclear envelope assembly, which ultimately lead to DNA damage accumulation and chromosome instability (3). Thus, mutations in the gene encoding lamin A (an essential component of the nuclear envelope) or in Zmpste24 (encoding a metalloproteinase involved in the maturation of lamin A) are responsible for several devastating human progeroid syndromes, including Hutchinson-Gilford progeria, atypical Werner syndrome, restrictive dermopathy, and mandibuloacral dysplasia (3)(4)(5)(6)(7). The elucidation of the molecular mechanisms underlying these diseases has been facilitated by the generation and analysis of Lmna-and Zmpste24-deficient mice, which exhibit profound nuclear architecture abnormalities and multiple histopathological defects that phenocopy human progeroid syndromes (8)(9)(10)(11)(12).…”

mentioning

confidence: 99%

Insulin-like growth factor 1 treatment extends longevity in a mouse model of human premature aging by restoring somatotroph axis function

Mariño¹,

Ugalde²,

Fernández³

et al. 2010

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

128

140

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Zmpste24 (also called FACE-1) is a metalloproteinase involved in the maturation of lamin A, an essential component of the nuclear envelope. Zmpste24-deficient mice exhibit multiple defects that phenocopy human accelerated aging processes such as HutchinsonGilford progeria syndrome. In this work, we report that progeroid Zmpste24 -/− mice present profound transcriptional alterations in genes that regulate the somatotroph axis, together with extremely high circulating levels of growth hormone (GH) and a drastic reduction in plasma insulin-like growth factor 1 (IGF-1). We also show that recombinant IGF-1 treatment restores the proper balance between IGF-1 and GH in Zmpste24 -/− mice, delays the onset of many progeroid features, and significantly extends the lifespan of these progeroid animals. Our findings highlight the importance of IGF/GH balance in longevity and may be of therapeutic interest for devastating human progeroid syndromes associated with nuclear envelope abnormalities.

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Human progeroid syndromes, aging and cancer: new genetic and epigenetic insights into old questions

Cited by 76 publications

References 138 publications

Loss of A-type lamins and genomic instability

Loss of A-type lamins and genomic instability

Analysis of Prelamin A Biogenesis Reveals the Nucleus to be a CaaX Processing Compartment

Insulin-like growth factor 1 treatment extends longevity in a mouse model of human premature aging by restoring somatotroph axis function

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