Fig. 3. Updated model of cell-cycle perturbation by the HPV oncogenes E6 and E7.

As proposed by McLaughlin-Drubin, Munger and colleagues, E7 induces the expression of lysine demethylases KDM6A and KDM6B, which in turn leads to the upregulation of CDKN1A (p21^CIP) and CDKN2A (p14^ARF and p16^INK4A), respectively. HPV⁺ cancer cells become dependent on the ongoing expression of p16^INK4A and p21^CIP, with the former acting to limit CDK4/6–cyclin D activity and the latter restraining proliferating cell nuclear antigen (PCNA) activity to avoid lethal replication stress (refs^83,86,87,89). Cell-cycle inhibitory proteins (p16^INK4A and p21^CIP1), upon which human papillomavirus (HPV)-transformed cells become dependent, are starred.