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Unscheduled DNA replication origin activation at inserted HPV 18 sequences in a HPV ‐18/ MYC amplicon
Author(s) -
Conti Chiara,
Herrick John,
Bensimon Aaron
Publication year - 2007
Publication title -
genes, chromosomes and cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.754
H-Index - 119
eISSN - 1098-2264
pISSN - 1045-2257
DOI - 10.1002/gcc.20448
Subject(s) - amplicon , biology , dna replication , genome instability , control of chromosome duplication , genetics , eukaryotic dna replication , replication factor c , dna replication factor cdt1 , gene duplication , dna , licensing factor , microbiology and biotechnology , carcinogenesis , semiconservative replication , origin recognition complex , origin of replication , gene , dna damage , polymerase chain reaction
Oncogene amplification is a critical step leading to tumorigenesis, but the underlying mechanisms are still poorly understood. Despite data suggesting that DNA replication is a major source of genomic instability, little is known about replication origin usage and replication fork progression in rearranged regions. Using a single DNA molecule approach, we provide here the first study of replication kinetics on a previously characterized MYC/papillomavirus (HPV18) amplicon in a cervical cancer. Using this amplicon as a model, we investigated the role DNA replication control plays in generating amplifications in human cancers. The data reveal severely perturbed DNA replication kinetics in the amplified region when compared with other regions of the same genome. It was found that DNA replication is initiated from both genomic and viral sequences, resulting in a higher median frequency of origin firings. In addition, it was found that the higher initiation frequency was associated with an equivalent increase in the number of stalled replication forks. These observations raise the intriguing possibility that unscheduled replication origin activation at inserted HPV-18 viral DNA sequences triggers DNA amplification in this cancer cell line and the subsequent overexpression of the MYC oncogene.