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. (c) 2007 Elsevier Inc. All rights reserved.

Drugs affecting prelamin A processing: Effects on heterochromatin organization / E., Mattioli; M., Columbaro; C., Capanni; S., Santi; N. M., Maraldi; M. R., D'Apice; G., Novelli; Riccio, Massimo; S., Squarzoni; R., Foisner; G., Lattanzi. - In: EXPERIMENTAL CELL RESEARCH. - ISSN 0014-4827. - STAMPA. - 314:3(2008), pp. 453-462. [10.1016/j.yexcr.2007.11.012]

Drugs affecting prelamin A processing: Effects on heterochromatin organization

RICCIO, Massimo;
2008

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 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. (c) 2007 Elsevier Inc. All rights reserved.
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Drugs affecting prelamin A processing: Effects on heterochromatin organization / E., Mattioli; M., Columbaro; C., Capanni; S., Santi; N. M., Maraldi; M. R., D'Apice; G., Novelli; Riccio, Massimo; S., Squarzoni; R., Foisner; G., Lattanzi. - In: EXPERIMENTAL CELL RESEARCH. - ISSN 0014-4827. - STAMPA. - 314:3(2008), pp. 453-462. [10.1016/j.yexcr.2007.11.012]
E., Mattioli; M., Columbaro; C., Capanni; S., Santi; N. M., Maraldi; M. R., D'Apice; G., Novelli; Riccio, Massimo; S., Squarzoni; R., Foisner; G., Lattanzi
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/11380/595659
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