Cancer is a multi-faceted disease that has the capacity to stem from an array cell types. One particular subtype of cancers that originate in epithelial tissues, termed ‘carcinomas’ or epithelial cancers, remain largely represented in both cancer diagnosis and mortality. Despite high incidence rates, the exact aetiology of these cancers remains unknown. Indeed, carcinomas often present with characteristic hallmark changes including altered cell morphology, a loss of cell polarity and tissue disorganization. Using high-throughput functional screening, our lab identified ZYG11A as a novel regulator of epithelial cell morphology. Current literature has described roles for ZYG11A in the regulation of cell cycle and polarity in C. Elegans and is thought to act as a substrate recognition subunit (SRS), important in targeting proteins for ubiquitin mediated degradation via the S26 proteasome. In terms of these functions in a mammalian context, very little is known about ZYG11A or its targets. Furthermore, there is also little information on the function of other ZYG11 family members (ZYG11B and ZER1) and their genetic and functional relationship to one another. Here, we describe a phenotypically clustered network of ZYG11A related genes acquired via a boutique siRNA functional genomic screen and high content immunofluorescence using MCF10A cells. Interestingly, the phenotypes vary between the ZYG11 family members, with the most prominent changes seen in ZYG11A knockdown. Preliminary qRT-PCR data also suggests compensation between the family members when each is knocked down. As previously mentioned, ZYG11A is thought to act as an SRS which targets proteins for degradation. Parallel to high-throughput screening methods, we also provide a method for the identification of ZYG11A substrates. Through the implementation of proximity-dependent biotin labelling and mass spectrometry analysis, we aim to use these candidates to delineate and validate the ubiquitination targets and pathways regulated by ZYG11A (and other family members) that contribute to the regulation of cell polarity and normal cell morphology.