Alterations in mitosis and cell cycle progression caused by a mutant lamin A known to accelerate human aging

T Dechat, T Shimi, SA Adam… - Proceedings of the …, 2007 - National Acad Sciences
T Dechat, T Shimi, SA Adam, AE Rusinol, DA Andres, HP Spielmann, MS Sinensky…
Proceedings of the National Academy of Sciences, 2007National Acad Sciences
Mutations in the gene encoding nuclear lamin A (LA) cause the premature aging disease
Hutchinson–Gilford Progeria Syndrome. The most common of these mutations results in the
expression of a mutant LA, with a 50-aa deletion within its C terminus. In this study, we
demonstrate that this deletion leads to a stable farnesylation and carboxymethylation of the
mutant LA (LAΔ50/progerin). These modifications cause an abnormal association of
LAΔ50/progerin with membranes during mitosis, which delays the onset and progression of …
Mutations in the gene encoding nuclear lamin A (LA) cause the premature aging disease Hutchinson–Gilford Progeria Syndrome. The most common of these mutations results in the expression of a mutant LA, with a 50-aa deletion within its C terminus. In this study, we demonstrate that this deletion leads to a stable farnesylation and carboxymethylation of the mutant LA (LAΔ50/progerin). These modifications cause an abnormal association of LAΔ50/progerin with membranes during mitosis, which delays the onset and progression of cytokinesis. Furthermore, we demonstrate that the targeting of nuclear envelope/lamina components into daughter cell nuclei in early G1 is impaired in cells expressing LAΔ50/progerin. The mutant LA also appears to be responsible for defects in the retinoblastoma protein-mediated transition into S-phase, most likely by inhibiting the hyperphosphorylation of retinoblastoma protein by cyclin D1/cdk4. These results provide insights into the mechanisms responsible for premature aging and also shed light on the role of lamins in the normal process of human aging.
National Acad Sciences