Abstract
The metazoan nucleus is equipped with a meshwork of intermediate filament proteins called the A- and B-type lamins. Lamins lie beneath the inner nuclear membrane and serve as a nexus to maintain the architectural integrity of the nucleus, chromatin organization, DNA repair and replication and to regulate nucleocytoplasmic transport. Perturbations or mutations in various components of the nuclear lamina result in a large spectrum of human diseases collectively called laminopathies. One of the most well-characterized laminopathies is Hutchinson–Gilford progeria (HGPS), a rare segmental premature aging syndrome that resembles many features of normal human aging. HGPS patients exhibit alopecia, skin abnormalities, osteoporosis and succumb to cardiovascular complications in their teens. HGPS is caused by a mutation in LMNA, resulting in a mutated form of lamin A, termed progerin. Progerin expression results in a myriad of cellular phenotypes including abnormal nuclear morphology, loss of peripheral heterochromatin, transcriptional changes, DNA replication defects, DNA damage and premature cellular senescence. A key challenge is to elucidate how these different phenotypes are causally and mechanistically linked. In this mini-review, we highlight some key findings and present a model on how progerin-induced phenotypes may be temporally and mechanistically linked.
Highlights
Aging can be defined as a gradual deterioration of cell and tissue function, resulting in an elevated risk of developing a large number of chronic illnesses
Progeroid syndromes can be classified into two main groups: The first group is caused by defects in DNA repair pathways or impaired telomere maintenance and includes Werner syndrome (WS), xeroderma pigmentosum (XP), Bloom syndrome (BS), Nijmegen breakage syndrome (NBS), Cockayne Syndrome (CS), Rothmund–Thomson syndrome (RTS), ataxia telangiectasia (AT), Fanconi anemia (FA), dyskeratosis congenita (DC) and Hoyeraal–Hreidarsson syndrome (HHS)
The second group is caused by mutations in components of the nuclear lamina and is represented by Hutchinson–Gilford progeria syndrome (HGPS), restrictive dermopathy (RD), Néstor–Guillermo progeria syndrome (NGPS) and mandibuloacral dysplasia (MAD) [6,7,8]
Summary
Aging can be defined as a gradual deterioration of cell and tissue function, resulting in an elevated risk of developing a large number of chronic illnesses. Original studies revealed that HGPS patient cells and various human cells expressing progerin develop nuclear abnormalities, loss of peripheral heterochromatin and a thickening of the nuclear lamina [35,36,37]. By expressing progerin during different cell cycle stages, it was recently shown that progerin triggers heterochromatin decompaction in growth-arrested (G0) cells, whilst DNA damage accumulates exclusively during DNA replication, separating these two phenotypes [48].
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