Alterations in mitosis and cell cycle progression caused by a mutant lamin A known to accelerate human aging
Journal - PNAS
Mutations in the gene encoding nuclear lamin A (LA) cause thepremature aging disease Hutchinson–Gilford Progeria Syndrome.The most common of these mutations results in the expressionof a mutant LA, with a 50-aa deletion within its C terminus.In this study, we demonstrate that this deletion leads to astable farnesylation and carboxymethylation of the mutant LA(LA50/progerin). These modifications cause an abnormal associationof LA50/progerin with membranes during mitosis, which delaysthe onset and progression of cytokinesis. Furthermore, we demonstratethat the targeting of nuclear envelope/lamina components intodaughter cell nuclei in early G1 is impaired in cells expressingLA50/progerin. The mutant LA also appears to be responsiblefor defects in the retinoblastoma protein-mediated transitioninto S-phase, most likely by inhibiting the hyperphosphorylationof retinoblastoma protein by cyclin D1/cdk4. These results provideinsights into the mechanisms responsible for premature agingand also shed light on the role of lamins in the normal processof human aging.
The authors declare no conflict of interest.
This article contains supporting information online at www.pnas.org/cgi/content/full/0700854104/DC1.© 2007 by The National Academy of Sciences of the USA
|Keywords : ||cell division • nuclear lamins • nuclear structure • progeria • protein farnesylation|