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

Thomas Dechat, Takeshi Shimi, Stephen A. Adam, Antonio E. Rusinol, Douglas A. Andres, H. Peter Spielmann, Michael S. Sinensky, Robert D. Goldman*

*Corresponding author for this work

Research output: Contribution to journalArticle

184 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)4955-4960
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume104
Issue number12
DOIs
StatePublished - Mar 20 2007

Keywords

  • Cell division
  • Nuclear lamins
  • Nuclear structure
  • Progeria
  • Protein farnesylation

ASJC Scopus subject areas

  • General

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