Lamins Are Reversibly Disassembled by Phosphorylation During Mitosis

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For the nuclear envelope to be broken down as cells go from prophase to prometaphase during mitosis, the nuclear lamina has to be disassembled. As we discuss in Chapter 19, protein kinases called mitotic CDKs drive cells into mitosis, and one of their substrates is the lamins. Phosphorylation of lamins A, B and C results in disassembly of the intermediate filament lattice into lamin dimers. Due to their C-terminal prenylation, lamin B dimers remain associated with the nuclear membrane. Depolymerization of the nuclear lamin filaments leads to the disintegration of the nuclear lamina meshwork and contributes to disassembly of the nuclear envelope. Later in mitosis (telophase), removal of the phosphates by specific phosphatases promotes lamin reassembly, which is critical to re-formation of a nuclear envelope around the daughter chromosomes. The opposing actions of kinases and phosphatases thus provide a rapid mechanism for controlling the assembly state of lamin intermediate filaments. Other intermediate filaments undergo similar disassembly and reassembly in the cell cycle.

There are over 200 known mutations located throughout the human gene for lamin A that are known to cause diseases, collectively called laminopathies. These diseases include cardiomyopathies, muscular dystrophies, lipodystrophy, and aging-related progeria. Some of these mutations cause Emery-Dreifuss muscular dystrophy (EDMD), most likely because the fragile nuclei cannot stand the stress and strains in the muscle tissue, so these cells are the first to show symptoms. Other forms of EDMD have been traced to mutations in emerin, the lamin-binding membrane protein of the inner nuclear envelope, as well as a nesprin and a SUN protein. Yet other mutations in lamin A cause progeria—accelerated aging, such as Hutchison-Gilford progeria (“prematurely old”). It is still a mystery why different mutations in the same human gene can cause such a wide variety of diseases.