Human papillomaviruses (HPVs) are responsible for approximately 5% of human cancers, with cervical cancer being the principal disease. During persistent viral infection, for, as yet, unknown reasons, HPV life cycle collapses and viral genomes are randomly integrated into host chromosomes, leading to the uncontrolled expression of the viral oncoproteins, E6 and E7, whose activities lead to cellular transformation. Both A- and ß-E6 oncoproteins have an LXXLL binding motif, through which A-E6s interact with E6AP and ß-E6s bind MAML1. Both interactions are critical for the viral life cycle and HPV-mediated carcinogenesis. Our preliminary data suggest that A-E6s also bind MAML1, stabilising E6 protein in an E6AP-independent manner and affecting E6’s cellular distribution, resulting in increased proliferative and migratory capacity of HPV-18-positive HeLa cells. This suggests that the MAML1 interaction has a broader impact on HPV-induced malignancies, and opens new avenues of research that may give valuable information on E6 functions and involvement in modulating various cellular signalling pathways.We aim to investigate how cancer-causing E6, complexed with MAML1, can modulate Notch signaling and to determine the biological consequences of this process. Our approaches will be to find novel interacting partners of the HR E6/MAML1 complex, to analyse the biochemistry of E6’s regulation of Notch signaling via MAML1, and to link these processes to the viral life cycle and HPV-driven tumorigenesis.This project will provide important information that will help in further clarifying the basic biology of HPVs and how this affects HPV-induced oncogenesis. The results will determine if targeting the E6/MAML1 complex and its interactors might have any therapeutic potential in HPV-induced pathogenesis. Furthermore, they will provide a list of cellular substrates that could act as potential predictive markers for HPV-induced malignancies.