TY - JOUR
T1 - Drugs affecting prelamin A processing
T2 - Effects on heterochromatin organization
AU - Mattioli, Elisabetta
AU - Columbaro, Marta
AU - Capanni, Cristina
AU - Santi, Spartaco
AU - Maraldi, Nadir M.
AU - D'Apice, M. Rosaria
AU - Novelli, Giuseppe
AU - Riccio, Massimo
AU - Squarzoni, Stefano
AU - Foisner, Roland
AU - Lattanzi, Giovanna
PY - 2008/2/1
Y1 - 2008/2/1
N2 - 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.
AB - 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.
KW - 5-azadeoxycytidine
KW - AFCMe
KW - FTI-277
KW - Heterochromatin organization
KW - Prelamin A
UR - http://www.scopus.com/inward/record.url?scp=38349073319&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=38349073319&partnerID=8YFLogxK
U2 - 10.1016/j.yexcr.2007.11.012
DO - 10.1016/j.yexcr.2007.11.012
M3 - Article
C2 - 18093584
AN - SCOPUS:38349073319
VL - 314
SP - 453
EP - 462
JO - Experimental Cell Research
JF - Experimental Cell Research
SN - 0014-4827
IS - 3
ER -