Altered chromatin organization and SUN2 localization in mandibuloacral dysplasia are rescued by drug treatment

Abstract

Mandibuloacral dysplasia type A (MADA) is a rare laminopathy characterized by growth retardation, craniofacial anomalies, bone resorption at specific sites including clavicles, phalanges and mandibula, mottled cutaneous pigmentation, skin rigidity, partial lipodystrophy, and insulin resistance. The disorder is caused by recessive mutations of the LMNA gene encoding for A-type lamins. The molecular feature of MADA consists in the accumulation of the unprocessed lamin A precursor, which is detected at the nuclear rim and in intranuclear aggregates. Here, we report the characterization of prelamin A post-translational modifications in MADA cells that induce alterations in the chromatin arrangement and dislocation of nuclear envelope-associated proteins involved in correct nucleo-cytoskeleton relationships. We show that protein post-translational modifications change depending on the passage number, suggesting the onset of a feedback mechanism. Moreover, we show that treatment of MADA cells with the farnesyltransferase inhibitors is effective in the recovery of the chromatin phenotype, altered in MADA, provided that the cells are at low passage number, while at high passage number, the treatment results ineffective. Moreover, the distribution of the lamin A interaction partner SUN2, a constituent of the nuclear envelope, is altered by MADA mutations, as argued by the formation of a highly disorganized lattice. Treatment with statins partially rescues proper SUN2 organization, indicating that its alteration is caused by farnesylated prelamin A accumulation. Given the major role of SUN1 and SUN2 in the nucleo-cytoskeleton interactions and in regulation of nuclear positioning in differentiating cells, we hypothesise that mechanisms regulating nuclear membrane–centrosome interplay and nuclear movement may be affected in MADA fibroblasts.Electronic supplementary materialThe online version of this article (doi:10.1007/s00418-012-0977-5) contains supplementary material, which is available to authorized users.

SUN2 Overexpression Deforms Nuclear Shape and Inhibits HIV

“…This accumulation of SUN1 in the nuclear envelope was implicated in nuclear shape defects in Lamin A-deficient fibroblasts, since SUN1 knockdown reversed these defects (84). Furthermore, both SUN1 and SUN2 have been proposed to play roles in the pathology of various laminopathies in vivo (86)(87)(88)(89). It is noteworthy, then, that the nucleoplasmic domain of SUN2, which is required for the interaction of SUN2 with Lamin A (35), is essential for the formation of flower-like nuclei in CHME cells.…”

Potential therapeutic effects of the MTOR inhibitors for preventing ageing and progeria‐related disorders

“…Progerin is toxic to cells and causes nuclear dysmorphism and a severe loss of heterochromatin , mislocalization or loss of chromatin‐associated proteins such as the DNA‐bridging factor barrier‐to‐autointegration factor (BAF) and the DNA damage repair proteins poly(ADP‐ribose) polymerase 1 (PARP1) and p53 binding protein 1 (53BP1) , and accumulation of irreparable DNA damage . The same effects are observed in other progeroid syndromes featuring accumulation of farnesylated prelamin A, such as mandibuloacral dysplasia type A and B (MADA and MADB, respectively) and atypical Werner syndrome (A‐WS) . MADA is a rare disease characterized by growth retardation, bone resorption at specific sites (including the clavicles, phalanges and mandible), mottled cutaneous pigmentation, skin rigidity, partial lipodystrophy and insulin resistance.…”

“…For instance, mutated prelamin A accumulates in MADA cells, and prelamin A levels increase in vitro with the number of passages in culture and in vivo with the age of the patients, contributing to a worsening of the disease . Two forms of prelamin A accumulate in MADA cells . However, while nonfarnesylated prelamin A is, in part, degraded through autophagy, farnesylated prelamin A accumulates to toxic levels.…”

Rapamycin treatment of Mandibuloacral Dysplasia cells rescues localization of chromatin-associated proteins and cell cycle dynamics

“…RD cells feature accumulation of prelamin A and complete absence of mature lamin A, due to homozygous mutations of the FACE1 gene, which impair the activity of the prelamin A endoprotease ZMPSTE24 [ 9 , 10 ]. Accumulation of prelamin A at lower levels occurs in MADA [ 11 ] and it has been associated with recruitment of the adipocyte transcription factor SREBP1 in the nuclear periphery and impaired nuclear transactivation activity [ 12 ]. Analogous mechanisms of transcription factor sequestration at the nuclear rim have been reported for cFos, which associates with mature lamin A [ 13 ], Sp1, which binds prelamin A [ 14 ] and Oct-1, which is retained by lamin B1 [ 15 ].…”