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 ultimately promoting viral integration and cervical cancer.
King
Lauren E
LE
Institute of Comparative Medicine, University of Glasgow Faculty of Veterinary, Medicine, Glasgow, G61 1QH, UK.
Fisk
John C
JC
Dornan
Edward S
ES
Donaldson
Mary M
MM
Melendy
Thomas
T
Morgan
Iain M
IM
D000957:Antigens, Viral, Tumor / Q000235:genetics / Q000502:physiology; D002460:Cell Line; D053903:DNA Breaks, Double-Stranded; D004249:DNA Damage; D004261:DNA Replication / Q000235:genetics* / Q000502:physiology*; D004279:DNA, Viral / Q000096:biosynthesis / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics / Q000502:physiology; D005047:Etoposide / Q000494:pharmacology; D005260:Female; D042822:Genomic Instability; D052140:Human papillomavirus 11 / Q000235:genetics / Q000472:pathogenicity / Q000502:physiology; D006801:Humans; D027383:Papillomaviridae / Q000235:genetics* / Q000472:pathogenicity / Q000502:physiology*; D030361:Papillomavirus Infections / Q000235:genetics / Q000821:virology; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology; D002583:Uterine Cervical Neoplasms / Q000209:etiology / Q000235:genetics / Q000821:virology; D014764:Viral Proteins / Q000235:genetics* / Q000502:physiology*; D016662:Virus Integration / Q000235:genetics / Q000502:physiology; D014779:Virus Replication / Q000235:genetics / Q000502:physiology
D000957:Antigens, Viral, Tumor; D004279:DNA, Viral; D004268:DNA-Binding Proteins; C084304:E1 protein, Human papillomavirus type 11; C117355:E2 protein, Human papillomavirus type 11; D014764:Viral Proteins; D005047:Etoposide