Werner syndrome helicase modulates G4 DNA-dependent transcription and opposes mechanistically distinct senescence-associated gene expression programs

Abstract

Werner syndrome (WS) is a prototypic heritable adult human progeroid syndrome in which signs of premature aging are associated with genetic instability and an elevated risk of specific types of cancer. We have quantified mRNA and microRNA (miRNA) expression in WS patient fibroblasts, and in WRN-depleted fibroblasts. Genes down-regulated in WS patient fibroblasts were highly enriched in G-quadruplex (G4) DNA motifs. The strength, location and strand specificity of this association provide strong experimental evidence that G4 motifs or motif-dependent G-quadruplexes are bound by WRN in human cells to modulate gene expression. The expression of many miRNAs was perturbed by loss of WRN function. WRN depletion altered the expression of >500 miRNAs. miRNAs linked to cell signaling, genome stability assurance and tumorigenesis were among the small number of these miRNAs that were persistently altered in WS patient fibroblasts. An unexpected and highly distinct finding in WS cells was the coordinate over-expression of nearly all cytoplasmic tRNA synthetases and their associated AIMP proteins. Our results provide new insight into WS pathogenesis, and identify therapeutically accessible mechanisms that may drive disease pathogenesis in WS and in the general population.