Abstract
Roberts syndrome (RBS) is a human disease characterized by defects in limb and craniofacial development and growth and mental retardation. RBS is caused by mutations in ESCO2, a gene which encodes an acetyltransferase for the cohesin complex. While the essential role of the cohesin complex in chromosome segregation has been well characterized, it plays additional roles in DNA damage repair, chromosome condensation, and gene expression. The developmental phenotypes of Roberts syndrome and other cohesinopathies suggest that gene expression is impaired during embryogenesis. It was previously reported that ribosomal RNA production and protein translation were impaired in immortalized RBS cells. It was speculated that cohesin binding at the rDNA was important for nucleolar form and function. We have explored the hypothesis that reduced ribosome function contributes to RBS in zebrafish models and human cells. Two key pathways that sense cellular stress are the p53 and mTOR pathways. We report that mTOR signaling is inhibited in human RBS cells based on the reduced phosphorylation of the downstream effectors S6K1, S6 and 4EBP1, and this correlates with p53 activation. Nucleoli, the sites of ribosome production, are highly fragmented in RBS cells. We tested the effect of inhibiting p53 or stimulating mTOR in RBS cells. The rescue provided by mTOR activation was more significant, with activation rescuing both cell division and cell death. To study this cohesinopathy in a whole animal model we used ESCO2-mutant and morphant zebrafish embryos, which have developmental defects mimicking RBS. Consistent with RBS patient cells, the ESCO2 mutant embryos show p53 activation and inhibition of the TOR pathway. Stimulation of the TOR pathway with L-leucine rescued many developmental defects of ESCO2-mutant embryos. Our data support the idea that RBS can be attributed in part to defects in ribosome biogenesis, and stimulation of the TOR pathway has therapeutic potential.
Highlights
Cohesin is a protein complex that adheres sister chromatids from the time of their replication until their division [1,2]
Roberts syndrome and other diseases caused by mutations in cohesin are associated with differential gene expression
We report that mutations in ESCO2 are associated with p53 activation and inhibition of mTOR in human cells and zebrafish
Summary
Cohesin is a protein complex that adheres sister chromatids from the time of their replication until their division [1,2]. Cohesion between sister chromatids is facilitated by acetylation of the Smc subunit of the complex by the ECO1 acetyltransferase during S phase [3,4,5]. Human developmental syndromes such as Roberts syndrome (RBS) and Cornelia de Lange syndrome, termed cohesinopathies, arise from mutations in cohesin genes [6]. Previous studies have reported loss of ESCO2 acetyltransferase activity in RBS [13]. A previous report revealed that mutations in yeast ECO1 and human ESCO2 impaired ribosomal RNA (rRNA) production and protein synthesis in budding yeast and human immortalized RBS cells [14]. We hypothesized that defective ribosome biogenesis contributes to the etiology of the RBS disorder
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