Nucleolar and Ribosomal Dysfunction-A Common Pathomechanism in Childhood Progerias?

Abstract

The nucleolus organizes around the sites of transcription by RNA polymerase I (RNA Pol I). rDNA transcription by this enzyme is the key step of ribosome biogenesis and most of the assembly and maturation processes of the ribosome occur co-transcriptionally. Therefore, disturbances in rRNA transcription and processing translate to ribosomal malfunction. Nucleolar malfunction has recently been described in the classical progeria of childhood, Hutchinson-Gilford syndrome (HGPS), which is characterized by severe signs of premature aging, including atherosclerosis, alopecia, and osteoporosis. A deregulated ribosomal biogenesis with enlarged nucleoli is not only characteristic for HGPS patients, but it is also found in the fibroblasts of "normal" aging individuals. Cockayne syndrome (CS) is also characterized by signs of premature aging, including the loss of subcutaneous fat, alopecia, and cataracts. It has been shown that all genes in which a mutation causes CS, are involved in rDNA transcription by RNA Pol I. A disturbed ribosomal biogenesis affects mitochondria and translates into ribosomes with a reduced translational fidelity that causes endoplasmic reticulum (ER) stress and apoptosis. Therefore, it is speculated that disease-causing disturbances in the process of ribosomal biogenesis may be more common than hitherto anticipated.

Keywords: Cockayne syndrome; Hutchinson–Gilford Progeria syndrome; RNA polymerase I; aging; nucleolus; ribosome; translational fidelity; trichothiodystrophy.

Figure 1

Graphical representation of the presumed/shown functions of the Cockayne syndrome proteins (red) in RNA polymerase I transcription. The functions are (from upper left), de-methylation of the promoter, attraction of a histone-modifier, reinitiation of basal transcription, and stimulation of elongation.

Figure 2

Graphical illustration of the hypothesis: Disturbances in RNA polymerase I transcription result in rRNA processing defects, altered subunit composition, and reduced translational fidelity of the ribosomes. Misfolded proteins provoke ER stress and an UPR that affects ribosomal biogenesis.