The adenovirus El A C-terminal region restrains oncogenic transformation through interaction with three distinct cellular pro-tein complexes that include the DYRK1A/1B/HAN11 complex. The E6 proteins of beta-human papillomaviruses (beta-HPVs) also interact with the DYRK1/HAN11 complex. A variant of HPV5 E6 frequently found in epidermodysplasia verruciformis skin lesions interacted less efficiently with DYRK1A/HAN11. The E6 variant and E7 of HPV5 efficiently coimmortalized primary epi-thelial cells, suggesting that naturally arising variants may contribute potential oncogenic activities of beta-HPV E6 proteins. [ABSTRACT FROM AUTHOR]