Drugs affecting prelamin A processing: Effects on heterochromatin organization

Elisabetta Mattioli, Marta Columbaro, Cristina Capanni, Spartaco Santi, Nadir M. Maraldi, M. Rosaria D'Apice, Giuseppe Novelli, Massimo Riccio, Stefano Squarzoni, Roland Foisner, Giovanna Lattanzi

Research output: Contribution to journalArticlepeer-review

Abstract

Increasing interest in drugs acting on prelamin A has derived from the finding of prelamin A involvement in severe laminopathies. Amelioration of the nuclear morphology by inhibitors of prelamin A farnesylation has been widely reported in progeroid laminopathies. We investigated the effects on chromatin organization of two drugs inhibiting prelamin A processing by an ultrastructural and biochemical approach. The farnesyltransferase inhibitor FTI-277 and the non-peptidomimetic drug N-acetyl-S-farnesyl-l-cysteine methylester (AFCMe) were administered to cultured control human fibroblasts for 6 or 18 h. FTI-277 interferes with protein farnesylation causing accumulation of non-farnesylated prelamin A, while AFCMe impairs the last cleavage of the lamin A precursor and is expected to accumulate farnesylated prelamin A. FTI-277 caused redistribution of heterochromatin domains at the nuclear interior, while AFCMe caused loss of heterochromatin domains, increase of nuclear size and nuclear lamina thickening. At the biochemical level, heterochromatin-associated proteins and LAP2α were clustered at the nuclear interior following FTI-277 treatment, while they were unevenly distributed or absent in AFCMe-treated nuclei. The reported effects show that chromatin is an immediate target of FTI-277 and AFCMe and that dramatic remodeling of chromatin domains occurs following treatment with the drugs. These effects appear to depend, at least in part, on the accumulation of prelamin A forms, since impairment of prelamin A accumulation, here obtained by 5-azadeoxycytidine treatment, abolishes the chromatin effects. These results may be used to evaluate downstream effects of FTIs or other prelamin A inhibitors potentially useful for the therapy of laminopathies.

Original languageEnglish
Pages (from-to)453-462
Number of pages10
JournalExperimental Cell Research
Volume314
Issue number3
DOIs
Publication statusPublished - Feb 1 2008

Keywords

  • 5-azadeoxycytidine
  • AFCMe
  • FTI-277
  • Heterochromatin organization
  • Prelamin A

ASJC Scopus subject areas

  • Cell Biology

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