Journal
JOURNAL OF CELLULAR BIOCHEMISTRY
Volume 102, Issue 5, Pages 1149-1159Publisher
WILEY
DOI: 10.1002/jcb.21467
Keywords
lamin A; pre-lamin A; heterochromatin organization; HP1 alpha; LAP2 alpha
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Pre-lamin A undergoes subsequent steps of post-translational modification at its C-terminus, including farnesylation, methylation, and cleavage by ZMPSTE24 metalloprotease. Here, we show that accumulation of different intermediates of pre-lamin A processing in nuclei, induced by expression of mutated pre-lamin A, differentially affected chromatin organization in human fibroblasts. Unprocessed (non-farnesylated) pre-lamin A accumulated in intranuclear foci, caused the redistribution of LAP2alpha and of the heterochromatin markers HP1 alpha and trimethyl-K9-histone 3, and triggered heterochromatin localization in the nuclear interior. In contrast, the farnesylated and carboxymethylated lamin A precursor accumulated at the nuclear periphery and caused loss of heterochromatin markers and Lap2alpha in enlarged nuclei. Interestingly, pre-lamin A bound both HP1 alpha and LAP2alpha in vivo, but the farnesylated form showed reduced affinity for HP1 alpha. Our data show a link between pre-lamin A processing and heterochromatin remodeling and have major implications for understanding molecular mechanisms of human diseases linked to mutations in lamins.
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