INHIBITION OF CDK ACTIVITY AND PCNA-DEPENDENT DNA-REPLICATION BY P21 IS BLOCKED BY INTERACTION WITH THE HPV-16 E7 ONCOPROTEIN

p21 inhibits cyclin-dependent kinase (CDK) activity and proliferating cell nuclear antigen (PCNA)-dependent DNA replication by binding to CD K/cyclin complexes and to PCNA through distinct domains. The human pap illomavirus (HPV)-16 E7 oncoprotein (16E7) abrogated a DNA damage-indu ced cell cycle arrest in vivo, despite high levels of p21. Using cell lysates and purified proteins we show that 16E7 prevented p21 both fro m inhibiting CDK2/cyclin E activity and PCNA-dependent DNA replication , whereas the nononcogenic HPV-6 E7 had reduced effects. Inactivation of both inhibitory functions of p21 was attained through binding betwe en 16E7 and sequences in the carboxy-terminal end of p21 that overlap with the PCNA-binding site and the second p21 cyclin-binding motif. Th ese data imply that the carboxyl terminus of p21 simultaneously modula tes both CDK activity and PCNA-dependent DNA replication and that a si ngle protein, 16E7, can override this modulation to disrupt normal cel l cycle control.