Human Papillomaviruses (HPVs) are responsible for about 4.5% of human cancers worldwide. Expression of the HPV oncoproteins E6 and E7 drives HPV-mediated carcinogenesis. HPV E7 oncoproteins bind to host proteins to facilitate virus replication and drive cancer progression. Numerous interactors of the HPV E7 protein have been identified. However, it is unclear which interactors are responsible for the carcinogenic activity of HPV E7. A proteomics study of HPV E7-host protein interactions identified the cellular protein ZER1 as a binding partner of the E7 protein from HPV16, the genotype most frequently associated with human cancers. The HPV16 E7-ZER1 interaction is unique among HPV E7s tested to date. ZER1 is a substrate specificity factor for a CUL2-RING ubiquitin ligase. It is known that viral oncoproteins frequently redirect cellular targets for proteasomal degradation to reprogram the host cell. In my dissertation, I performed cell-based assays, particularly cell growth and soft agar assays, cancer dependency data analysis, and systematic approaches to determine whether ZER1 could enable some of the carcinogenic activity of HPV16 E7. I developed an HPV16 E7 mutant that cannot bind ZER1 and demonstrated that it is impaired in the ability to promote keratinocyte growth. Depleting ZER1 reduced the growth of HPV E7-expressing keratinocytes and the anchorage-independent growth of HPV-positive cervical cancer cells. Moreover, I found that CUL2ZER1 contribute to but are not the only factors required for HPV16 E7 to degrade RB1. Using cancer dependency data, I identified ZER1 and UBE3A as the only two genes essential in most of the HPV-positive but not HPV-negative cancer cell lines. I found that ZER1 is essential for the viability of many HPV-positive cancer cells, regardless of the specific HPV genotype. Our systematic analysis identified cellular proteins that interact with ZER1. I also identified changes in host protein abundance in HPV16 E7-expressing keratinocytes, some of which could depend on ZER1 binding to HPV16 E7. In conclusion, my dissertation demonstrates that ZER1 contributes to HPV-mediated carcinogenesis and reveals an opportunity to target ZER1 for therapeutic application against cancers caused by HPV.