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

doi:10.1073/pnas.0700854104

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

*Department of Cell and Molecular Biology, Feinberg School of Medicine, Northwestern University, 303 East Chicago Avenue, Chicago, IL 60611;
^†Department of Biochemistry and Molecular Biology, James H. Quillen College of Medicine, East Tennessee State University, Box 70581,Johnson City, TN 37614; and
^‡Departments of Molecular and Cellular Biochemistry and
^§Chemistry and
^¶Kentucky Center for Structural Biology, University of Kentucky, 741 South Limestone, Lexington, KY 40536

Communicated by Francis S. Collins, National Institutes of Health, Bethesda, MD, February 2, 2007 (received for review December 19, 2006)

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 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.

Footnotes

^‖To whom correspondence should be addressed. E-mail: r-goldman{at}northwestern.edu
Author contributions: T.D., T.S., A.E.R., M.S.S., and R.D.G. designed research; T.D., T.S., A.E.R., and M.S.S. performed research; S.A.A., D.A.A., and H.P.S. contributed new reagents/analytic tools; T.D., T.S., A.E.R., M.S.S., and R.D.G. analyzed data; and T.D., A.E.R., M.S.S., and R.D.G. wrote the paper.
The authors declare no conflict of interest.
This article contains supporting information online at www.pnas.org/cgi/content/full/0700854104/DC1.
Abbreviations:

AG,

anilinogeraniol;

FTase,

farnesyl transferase;

FTI,

FTase inhibitor;

HGPS,

Hutchinson–Gilford progeria syndrome;

LA,

lamin A;

LB,

B-type lamins;

LC,

lamin C;

LAΔ50/progerin,

mutant LA in HGPS cells;

NEBD,

nuclear envelope breakdown;

Rb,

retinoblastoma protein.