Human papillomavirus E1 and E2 mediated DNA replication is not arrested by DNA damage signalling

Integration of human papillomaviruses into that of the host promotes genomic instability and progression to cancer: factors that promote integration remain to be fully identified. DNA damage agents can promote double strand breaks during DNA replication providing substrates for integration and we investigated the ability of DNA damage to regulate HPV E1 and E2 mediated DNA replication. Results demonstrate that HPV E1 and E2 replication is not arrested following DNA damage, both in vivo and in vitro, while replication by SV40 Large T antigen is arrested and ATR is the candidate kinase for mediating the arrest. LTAg is a target for PIKK DNA damage signalling kinases, while E1 is not. We propose that the failure of E1 to be targeted by PIKKs allows HPV replication in the presence of DNA damaging agents. Such replication will result in double strand breaks in the viral genome ultimatE1y promoting viral integration and cervical cancer. (C) 2010 E1sevier Inc. All rights reserved.