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Published on: March 12, 2020
Drugs affecting prelamin A processing: effects on heterochromatin organization
Elisabetta Mattioli1, Marta Columbaro, Cristina Capanni
1IGM-CNR, Unit of Bologna, c/o IOR, Via di Barbiano 1/10 I-40136 Bologna, Italy.
Experimental Cell Research
|December 21, 2007
Summary
Two drugs targeting prelamin A processing, FTI-277 and AFCMe, significantly altered chromatin organization in human cells. These prelamin A inhibitors demonstrate potential for treating laminopathies by remodeling nuclear heterochromatin.
Area of Science:
- Cell Biology
- Molecular Biology
- Genetics
Background:
- Prelamin A is implicated in severe laminopathies.
- Inhibitors of prelamin A farnesylation can improve nuclear morphology in progeroid laminopathies.
Purpose of the Study:
- To investigate the effects of two prelamin A processing inhibitors, FTI-277 and AFCMe, on chromatin organization.
- To elucidate the role of prelamin A accumulation in drug-induced chromatin remodeling.
Main Methods:
- Treatment of cultured human fibroblasts with FTI-277 or AFCMe for 6 or 18 hours.
- Ultrastructural and biochemical analyses to assess nuclear morphology and protein distribution.
- Inhibition of prelamin A accumulation using 5-azadeoxycytidine.
Main Results:
- FTI-277 caused heterochromatin redistribution to the nuclear interior.
- AFCMe led to loss of heterochromatin, increased nuclear size, and lamina thickening.
- Both drugs induced clustering or altered distribution of heterochromatin-associated proteins and LAP2 alpha, dependent on prelamin A accumulation.
Conclusions:
- Chromatin is an immediate target of FTI-277 and AFCMe.
- Prelamin A accumulation is partly responsible for the observed chromatin remodeling.
- These findings support the evaluation of prelamin A inhibitors for laminopathy therapy.
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