Uev1A counteracts oncogenic <i>Ras</i> stimuli in both polyploid and diploid cells.

Abstract

Oncogenic <i>Ras</i> is known to induce DNA replication stress, leading to cellular senescence or death. In contrast, we found that it can also trigger polyploid <i>Drosophila</i> ovarian nurse cells to die by inducing aberrant division stress. To explore intrinsic protective mechanisms against this specific form of cellular stress, here, we conducted a genome-wide genetic screen and identified the E2 enzyme Uev1A as a key protector. Reducing its expression levels exacerbates the nurse cell death induced by oncogenic <i>Ras</i>, while overexpressing it or its human homologs, UBE2V1 and UBE2V2, mitigates this effect. Although Uev1A is primarily known for its non-proteolytic functions, our studies demonstrate that it collaborates with the E3 APC/C complex to mediate the proteasomal degradation of Cyclin A, a key cyclin that drives cell division. Furthermore, Uev1A and UBE2V1/2 also counteract oncogenic <i>Ras</i>-driven tumorigenesis in diploid cells, suppressing the overgrowth of germline tumors in <i>Drosophila</i> and human colorectal tumor xenografts in nude mice, respectively. Remarkably, elevated expression levels of UBE2V1/2 correlate with improved survival rates in human colorectal cancer patients harboring oncogenic <i>KRAS</i> mutations, indicating that their upregulation could represent a promising therapeutic strategy.