Increased activity of PRMT5-MEP50 complex improves survival of chromosomally unstable cancer cells by increasing tolerance to protein aggregation and proteotoxicity

Abstract

Most cancers display chromosomal instability (CIN), a condition that leads to increased rates of chromosome missegregation and thus yields aneuploidy. CIN and aneuploidy are detrimental to healthy cells and therefore, aneuploid cells rely on aneuploidy-tolerating mechanisms to adopt a malignant fate. We previously found PRMT5 to be frequently amplified in a mouse model for aneuploid T cell lymphoblastic lymphoma. In this study, we investigated a possible role of PRMT5 as an aneuploidy tolerating gene. We report that PRMT5 is prone to aggregation when expressed at supra-stoichiometric levels compared to its obligate partner protein MEP50 (methylosome protein 50, WDR77). Intriguingly, we also find that protein aggregation, induced by CIN, is mitigated by jointly increased expression of PRMT5 and MEP50. Accordingly, concomitant PRMT5:MEP50 expression renders cancer cells less sensitive to proteasome inhibitors and CIN while inhibition sensitizes cells to CIN. Our findings provide a possible explanation for why PRMT5 and MEP50 display increased expression, particularly in aneuploid cancers and might reveal a targetable vulnerability of aneuploid cancer.