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.
Pre-lamin a processing is linked to heterochromatin organization / G., Lattanzi; M., Columbaro; E., Mattioli; V., Cenni; D., Camozzi; M., Wehnert; S., Santi; Riccio, Massimo; R., Del Coco; N. M., Maraldi; S., Squarzoni; R., Foisner; C., Capanni. - In: JOURNAL OF CELLULAR BIOCHEMISTRY. - ISSN 0730-2312. - STAMPA. - 102:5(2007), pp. 1149-1159. [10.1002/jcb.21467]
Pre-lamin a processing is linked to heterochromatin organization
RICCIO, Massimo;
2007
Abstract
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.Pubblicazioni consigliate
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