Drugs affecting prelamin A processing: effects on heterochromatin organization.
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 LAP2 alpha 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.
Mattioli
Elisabetta
E
IGM-CNR, Unit of Bologna, c/o IOR, Via di Barbiano 1/10 I-40136 Bologna, Italy.
Columbaro
Marta
M
Capanni
Cristina
C
Santi
Spartaco
S
Maraldi
Nadir M
NM
D'Apice
M Rosaria
MR
Novelli
Giuseppe
G
Riccio
Massimo
M
Squarzoni
Stefano
S
Foisner
Roland
R
Lattanzi
Giovanna
G
D000111:Acetylcysteine / Q000031:analogs & derivatives / Q000494:pharmacology; D000328:Adult; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology; D001374:Azacitidine / Q000031:analogs & derivatives / Q000494:pharmacology; D002467:Cell Nucleus / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure; D002478:Cells, Cultured; D042002:Chromatin Assembly and Disassembly / Q000187:drug effects* / Q000235:genetics; D004268:DNA-Binding Proteins / Q000187:drug effects / Q000378:metabolism; D000077209:Decitabine; D004791:Enzyme Inhibitors / Q000494:pharmacology; D051231:Farnesyltranstransferase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D006570:Heterochromatin / Q000187:drug effects* / Q000235:genetics / Q000648:ultrastructure; D006801:Humans; D034904:Lamin Type A / Q000187:drug effects / Q000378:metabolism; D008565:Membrane Proteins / Q000187:drug effects / Q000378:metabolism; D008715:Methionine / Q000031:analogs & derivatives / Q000494:pharmacology; D034881:Nuclear Lamina / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D009687:Nuclear Proteins / Q000187:drug effects* / Q000378:metabolism; D011498:Protein Precursors / Q000187:drug effects* / Q000378:metabolism; D017368:Protein Prenylation / Q000187:drug effects* / Q000502:physiology
D000964:Antimetabolites, Antineoplastic; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; C096856:FTI 277; D006570:Heterochromatin; D034904:Lamin Type A; D008565:Membrane Proteins; D009687:Nuclear Proteins; D011498:Protein Precursors; C093413:lamina-associated polypeptide 2; C090764:prelamin A; D000077209:Decitabine; D008715:Methionine; D051231:Farnesyltranstransferase; C068268:N-acetyl-S-farnesylcysteine; D001374:Azacitidine; D000111:Acetylcysteine