Progerin impairs chromosome maintenance by depleting CENP-F from metaphase kinetochores in Hutchinson-Gilford progeria fibroblasts

Oncotarget. 2016 Apr 26;7(17):24700-18. doi: 10.18632/oncotarget.8267.


Hutchinson-Gilford progeria syndrome (HGPS, OMIM 176670) is a rare premature aging disorder that leads to death at an average age of 14.7 years due to myocardial infarction or stroke. The most common mutation in HGPS is at position G608G (GGC>GGT) within exon 11 of the LMNA gene. This mutation results in the deletion of 50 amino acids at the carboxyl-terminal tail of prelamin A, producing a truncated farnesylated protein called progerin. Lamins play important roles in the organization and structure of the nucleus. The nuclear build-up of progerin causes severe morphological and functional changes in interphase HGPS cells. In this study, we investigated whether progerin elicits spatiotemporal deviations in mitotic processes in HGPS fibroblasts. We analyzed the nuclear distribution of endogenous progerin during mitosis in relation to components of the nuclear lamina, nuclear envelope (NE) and nuclear pores. We found that progerin caused defects in chromosome segregation as early as metaphase, delayed NE reformation and trapped lamina components and inner NE proteins in the endoplasmic reticulum at the end of mitosis. Progerin displaced the centromere protein F (CENP-F) from metaphase chromosome kinetochores, which caused increased chromatin lagging, binucleated cells and genomic instability. This accumulation of progerin-dependent defects with each round of mitosis predisposes cells to premature senescence.

Keywords: CENP-F; Hutchinson-Gilford progeria; lamin; mitosis; progerin.

MeSH terms

  • Amino Acid Sequence
  • Cell Line
  • Chromosomal Proteins, Non-Histone / deficiency
  • Chromosomal Proteins, Non-Histone / genetics
  • Chromosomal Proteins, Non-Histone / metabolism*
  • Fibroblasts / metabolism*
  • HeLa Cells
  • Humans
  • Immunohistochemistry
  • Kinetochores / metabolism*
  • Lamin Type A / metabolism*
  • Microfilament Proteins / deficiency
  • Microfilament Proteins / genetics
  • Microfilament Proteins / metabolism*
  • Mitosis / genetics
  • Progeria / genetics*
  • Progeria / metabolism
  • Progeria / pathology
  • Transfection


  • Chromosomal Proteins, Non-Histone
  • Lamin Type A
  • Microfilament Proteins
  • centromere protein F
  • prelamin A