REG gamma proteasome activator is involved in the maintenance of chromosomal stability

REG gamma is a member of the 11S regulatory particle that activates the 20S proteasome. Studies in REG gamma deficient mice indicated an additional role for this protein in cell cycle regulation and proliferation control. In this paper we demonstrate that REG gamma protein is equally expressed throughout the cell cycle, but undergoes a distinctive subcellular localization at mitosis. Thus, while in interphase cells REG gamma is nuclear, in telophase cells it localizes on chromosomes, suggesting a role in mitotic progression. Furthermore, we found that REG gamma overexpression weakens the mitotic arrest induced by spindle damage, allowing premature exit from mitosis, whereas REG gamma depletion has the opposite effect, thus reflecting a new REG gamma function, unrelated to its role as proteasome activator. Additionally, we found that primary cells from REG gamma(-/-) mice and human fibroblasts with depleted expression of REG gamma or overexpressing a dominant negative mutant unable to activate the 20S proteasome, demonstrated a marked aneuploidy (chromosomal gains and losses), supernumerary centrosomes and multipolar spindles. These findings thus underscore a previously uncharacterized function of REG gamma in centrosome and chromosomal stability maintenance.