Alterations in Mitosis and Cell Cycle Progression Caused by a Mutant Lamin a Known to Accelerate Human Aging
Document Type
Article
Publication Date
3-20-2007
Description
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 LAΔ507 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 G 1 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.
Citation Information
Dechat, Thomas; Shimi, Takeshi; Adam, Stephen A.; Rusinol, Antonio E.; Andres, Douglas A.; Spielmann, H. Peter; Sinensky, Michael S.; and Goldman, Robert D.. 2007. Alterations in Mitosis and Cell Cycle Progression Caused by a Mutant Lamin a Known to Accelerate Human Aging. Proceedings of the National Academy of Sciences of the United States of America. Vol.104(12). 4955-4960. https://doi.org/10.1073/pnas.0700854104 PMID: 17360326 ISSN: 0027-8424