The 26S proteasome drives trinucleotide repeat expansions

Abstract

Trinucleotide repeat (TNR) expansion is the causa-tive mutation for at least 17 inherited neurological diseases. An important question in the field is which proteins drive the expansion process. This study reports that the multi-functional protein Sem1 is a novel driver of TNR expansions in budding yeast. Mutants of SEM1 suppress up to 90 % of expansions. Subsequent analysis showed that Sem1 facilitates expansions via its function in the 26S proteasome, a highly conserved multi-subunit complex with both proteolytic and non-pro-teolytic functions. The proteolytic function of the 26S proteasome is relevant to expansions, asmutation of additional proteasome components or treatment of yeast with a proteasome inhibitor suppressed CTGCAG expansions. The 26S proteasome also drives expansions in human cells. In a human astro-cytic cell line, siRNA-mediated knockdown of 26S proteasome subunits PSMC5 or PSMB3 reduced expansions. This expansion phenotype, both in yeast and human cells, is dependent on the proteo-lytic activity of the proteasome rather than a stress response owing to depletion of free ubiquitin. Thus, the 26S proteasome is a novel factor that drives expansions in both yeast and human cells by amech-anism involving protein degradation