The Laminopathies and the Insights They Provide into the Structural and Functional Organization of the Nucleus

Abstract

In recent years, our perspective on the cell nucleus has evolved from the view that it is a passive but permeable storage organelle housing the cell's genetic material to an understanding that it is in fact a highly organized, integrative, and dynamic regulatory hub. In particular, the subcompartment at the nuclear periphery, comprising the nuclear envelope and the underlying lamina, is now known to be a critical nexus in the regulation of chromatin organization, transcriptional output, biochemical and mechanosignaling pathways, and, more recently, cytoskeletal organization. We review the various functional roles of the nuclear periphery and their deregulation in diseases of the nuclear envelope, specifically the laminopathies, which, despite their rarity, provide insights into contemporary health-care issues. Expected final online publication date for the Annual Review of Genomics and Human Genetics, Volume 21 is August 31, 2020. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

Low lamin A levels enhance confined cell migration and metastatic capacity in breast cancer

“…In addition to providing mechanical stability, the nuclear lamina acts as a scaffold for interactions guiding the localization and assembly of protein complexes such as transcriptional regulators or other NE proteins, tethering and transcriptional silencing of regions of chromatin, and connecting the nuclear interior to the cytoskeleton via the Linker of Nucleoskeleton and Cytoskeleton (LINC) complex (Andres and Gonzalez, 2009;Gruenbaum and Foisner, 2015;Maurer and Lammerding, 2019). A critical role for lamin A/C in tissue function is supported by the multitude of mutations throughout the LMNA gene that cause human diseases (Schreiber and Kennedy, 2013;Wong and Stewart, 2020). Since lamins regulate diverse cellular characteristics, it is striking, but perhaps not surprising, that changes in lamin A/C expression have been documented in many types of human cancer (Bell and Lammerding, 2016;Dubik and Mai, 2020;Irianto et al, 2016b), including breast cancer (Alhudiri et al, 2019;Capo-chichi et al, 2011;Matsumoto et al, 2015;Wazir et al, 2013).…”

Lamin C regulates genome organization after mitosis

“…Lamins encoded by LMNA, LMNB1 and LMNB2 form networks of nuclear intermediate filaments as major components of the nucleoskeleton. Lamin filaments interact with key partners, including most nuclear membrane proteins, to form nuclear lamina networks that determine nuclear mechanics, modulate signaling and dynamically organize the genome [1][2][3][4][5][6] . Lamina networks interact with large regions of transcriptionally-silent heterochromatin in each cell type and customize the 3D configuration of individual chromosomes with respect to the nuclear envelope (NE).…”

Small-Molecule Therapeutic Perspectives for the Treatment of Progeria

“…This leads to the appearance of many cell defects, especially nuclear alterations, as would be expected from the fundamental structural role that lamin A plays in the nucleus. Progeroid cells display anomalous nuclear morphology and impaired nuclear functions, fundamentally due to the lack of the dynamic movement that HGPS belongs to a broader group of diseases called laminopathies [5], which are a consequence of different mutations in the LMNA gene. All of them result in a wide spectrum of overlapping disorders that comprise muscular dystrophies, a peripheral neuropathy, lipodystrophy syndromes, and accelerated aging disorders that share some of the features of progeria [6].…”