Lamin A precursor induces barrier-to-autointegration factor nuclear localization

Abstract

Lamin A, a protein component of the nuclear lamina, is synthesized as a precursor named prelamin A, whose multi-step maturation process involves different protein intermediates. As demonstrated in laminopathies such as familial partial lipodystrophy, mandibuloacral dysplasia, Werner syndrome, Hutchinson-Gilford progeria syndrome and restrictive dermopathy, failure of prelamin A processing results in the accumulation of lamin A protein precursors inside the nucleus which dominantly produces aberrant chromatin structure. To understand if nuclear lamina components may be involved in prelamin A chromatin remodeling effects, we investigated barrier-to-autointegration factor (BAF) localization and expression in prelamin A accumulating cells. BAF is a DNA-binding protein that interacts directly with histones, lamins and LEM-domain proteins and has roles in chromatin structure, mitosis and gene regulation. In this study, we show that the BAF heterogeneous localization between nucleus and cytoplasm observed in HEK293 cycling cells changes in response to prelamin A accumulation. In particular, we observed that the accumulation of lamin A, non-farnesylated prelamin A and farnesylated carboxymethylated lamin A precursors induce BAF nuclear translocation. Moreover, we show that the treatment of human fibroblasts with prelamin A interfering drugs results in similar changes. Finally, we report that the accumulation of progerin, a truncated form of farnesylated and carboxymethylated prelamin A identified in Hutchinson-Gilford progeria syndrome cells, induces BAF recruitment in the nucleus. These findings are supported by coimmunoprecipitation of prelamin A or progerin with BAF in vivo and suggest that BAF could mediate prelamin A-induced chromatin effects

Centenarian lamins: rapamycin targets in longevity

“…Our data add to the evidence that prelamin A is accumulated in normal smooth muscle cells during ageing as an effect of FACE1 downregulation (Ragnauth et al, 2010) and to our previously published data showing a physiological role of prelamin A Capanni et al, 2010;Mattioli et al, 2011). We envisage that a non-modulated, thus inappropriate, response mechanism is activated in laminopathies as a result of molecular defects.…”

Epigenetic Changes in Aging and Age-related Disease

“…Early DNA methylation alterations at ankyrin 1 (ANK1), disco-interacting protein 2 (DIP2A), rhomboid family member 2 (RHBDF2), ribosomal protein L13 (RPL13), SERPINF1 and SERPINF2 are connected to a network of known AD susceptibility genes and may have a role in the onset of AD [116]. In another study, two genes, SORBS3, involved in cell adhesion, and S100A2, a calcium binding protein, have been found to become progressively more methylated with age and their methylation becomes accelerated in patients with AD [95]. However, not all genes implicated in AD pathogenesis are associated with age-related changes in DNA methylation.…”

“…The consequences of such distortion are a loss of peripheral heterochromatin, rampant nuclear disorganization and nuclear lobulation or blebbing [89,94]. Of note, several proteins involved in maintaining nuclear architecture, such as barrier-to-autointegration factor (BAF) [95], inhibitor of growth protein 1 (ING1) [96] and D4Z4 [97], are also frequently lost in progeroid cells. In addition to aberrations in nuclear architecture, HGPS patients display a substantial down regulation of the histone variant γH2AX, an important marker of DNA repair.…”

Hutchinson–Gilford progeria syndrome through the lens of transcription

“…Notably, the 50-amino acids deletion that characterizes progerin does not interfere with progerin-BAF binding. Binding of BAF to progerin as well as to LA and prelamin A result in loss of BAF cytoplasmic pool, and in its partial dysfunction probably due to loss of BAF interactions with the chromatin-organizing protein RBBP4 (Capanni et al, 2010). Interestingly, a recessive mutation in BAF causes segmental premature-aging syndrome that resembles HGPS but lacks atherosclerosis (Puente et al, 2011).…”