318 A novel pathomechanism: are Cockayne syndrome and trichothiodystrophy ribosomopathies?

Abstract

The childhood premature aging diseases Cockayne syndrome(CS) and trichothiodystrophy (TTD) are attributed DNA-repair diseases as the affected genes code for DNA-repair proteins. However, no accumulating DNA-damage nor an elevated cancer incidence as a consequence of unrepaired DNA-damage has been reported in patients. The DNA-repair proteins are also involved in the key step of ribosomal biogenesis, transcription by RNA polymerase I. Here we investigated the cellular consequences of a disturbed ribosomal biogenesis and discovered that translational fidelity of the ribosomes of all patient cell lines tested is reduced. This might be due to rRNA processing defects in patient cells as detected by northern blots. Mass spectrometry analyses revealed that ribosomes from patient cells are instable when isolated under stringent conditions. The resulting reduced accuracy of the translation process produces misfolded proteins that provoke endoplasmic reticulum stress and an unfolded protein response that in turn represses transcription of RNA polymerase I and ribosomal biogenesis. This vicious circle can be disrupted by pharmaceutical chaperones offering a treatment opportunity for the affected children. Interestingly this pathomechanism, identified in CS-cells, is also active in cells of TTD patients that also suffer from retarded growth, microcephaly and premature aging. Loss of proteostasis due to an inaccurate translation has not been described in human pathology before and offers one plausible explanation for the developmental problems and premature aging characterising these children.