Elucidating the role of DDX27 in aneuploidy tolerance and stress response

​

Yonatan Eliezer, Tel-Aviv University

 

Aneuploidy, an imbalanced number of chromosomes or chromosome arms, is the most common genetic aberration in cancer and is associated with a worse prognosis. However, in non-transformed cells, aneuploidy imposes a substantial fitness cost, leading to cell cycle arrest and cell death. This cost results from several cellular stresses, including proteotoxic, metabolic, mitotic, and replication stress. Thus, for aneuploidy to be beneficial in cancer, tolerance mechanisms that allow cells to cope with these stresses must develop. In this study, we systematically investigated the cellular mechanisms that enable aneuploidy tolerance. We conducted large-scale analyses of gene expression, genetic, and pharmacological dependency datasets from human tumors and cancer cell lines. This analysis identified 55 genes associated with aneuploidy tolerance, primarily enriched for functions in ribosome biogenesis and translation, DNA repair, replication stress, and the p53 pathway. Notably, these align with known aneuploidy-induced stresses. A top hit was DDX27, an under-studied nucleolar RNA helicase with unclear function. We showed that DDX27 is consistently overexpressed in aneuploid cells across multiple isogenic systems, indicating that its upregulation is a common feature of aneuploidy. Furthermore, DDX27 knockout cells displayed increased sensitivity to chromosomal instability (CIN), highlighting its role in aneuploidy tolerance. Mechanistically, DDX27 facilitates nucleolar R-loop resolution, potentially by unwinding existing R-loops, thereby alleviating nucleolar stress. Our findings suggest nucleolar stress is an additional, previously uncharacterized aneuploidy-induced stress, upstream of known consequences of aneuploidy. Beyond its role in ribosome biogenesis, the nucleolus also contributes to DNA damage repair, chromosome segregation, and replication. Consistent with this, DDX27 knockdown cells showed reduced translation and ribosome biogenesis, increased DNA damage sensitivity, cell cycle arrest, and more mitotic aberrations. Overall, our findings identify DDX27 as a novel mediator of aneuploidy tolerance via nucleolar stress regulation, offering new insight into the interplay between nucleolar function and aneuploidy during tumorigenesis.