Cockayne syndrome mutation in XPG activate the integrated stress response

TL;DR

A mutation in the XPG gene causes Cockayne syndrome by activating a cellular stress response, leading to growth and neurological issues.

Contribution

The study identifies cellular stress response activation as a novel mechanism underlying Cockayne syndrome caused by XPG mutations.

Findings

XPG mutations in Cockayne syndrome lead to RNA polymerase I and rRNA maturation defects.

Cells show increased eIF2alpha phosphorylation and a shift to IRES translation, indicating stress response activation.

Disturbances in ribosomal biogenesis and translation control may contribute to Cockayne syndrome pathology.

Abstract

Xeroderma pigmentosum (XP) and Cockayne syndrome (CS) are diseases provoked by mutations in multifunctional proteins that are involved in DNA repair. DNA-repair deficiency explains the high cancer incidence of XP, whereas cancer-free CS, characterized by growth retardation, neurological degeneration, and premature aging does not present as a classical DNA-repair deficiency disorder. Here, we compared a severe combined XP/CS case provoked by XPG-mutation with an XP “only” patient cell line caused by mutation in the same XPG gene to carve out the pathogenic cellular disturbances that provoke CS. We identified RNA polymerase I transcription and rRNA maturation defects, a highly phosphorylated eukaryotic initiation factor 2 alpha (eIF2alpha), and a shift from cap- to internal ribosomal entry site (IRES) translation, indicating an activated integrated stress response in CS. Disturbances in ribosomal biogenesis and translational control might thus contribute to the development of CS.

The online version contains supplementary material available at 10.1007/s00439-025-02804-3.

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