RESUMO
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 LMNA gene 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.
Assuntos
Lamina Tipo A/metabolismo , Lamina Tipo B/metabolismo , Proteínas Nucleares/metabolismo , Progéria/genética , Precursores de Proteínas/metabolismo , Transcrição Gênica , Células-Tronco Adultas/metabolismo , Células-Tronco Adultas/patologia , Núcleo Celular/genética , Núcleo Celular/metabolismo , Montagem e Desmontagem da Cromatina , Reparo do DNA , Inativação Gênica , Humanos , Lamina Tipo A/genética , Lamina Tipo B/genética , Mecanotransdução Celular , Proteínas Nucleares/genética , Fenótipo , Progéria/metabolismo , Progéria/patologia , Precursores de Proteínas/genética , Telômero/genética , Telômero/metabolismoRESUMO
The nuclear lamina is a proteinaceous structure located underneath the inner nuclear membrane (INM), where it associates with the peripheral chromatin. It contains lamins and lamin-associated proteins, including many integral proteins of the INM, chromatin modifying proteins, transcriptional repressors and structural proteins. A fraction of lamins is also present in the nucleoplasm, where it forms stable complexes and is associated with specific nucleoplasmic proteins. The lamins and their associated proteins are required for most nuclear activities, mitosis and for linking the nucleoplasm to all major cytoskeletal networks in the cytoplasm. Mutations in nuclear lamins and their associated proteins cause about 20 different diseases that are collectively called laminopathies'. This review concentrates mainly on lamins, their structure and their roles in DNA replication, chromatin organization, adult stem cell differentiation, aging, tumorogenesis and the lamin mutations leading to laminopathic diseases.