Regulation of the Life Cycle of HPVs by Differentiation and the DNA Damage Response

Abstract

HPVs are the causative agents of cervical and other anogenital cancers. HPVs infect stratified epithelia and link their productive life cycles to cellular differentiation. Low levels of viral genomes are stably maintained in undifferentiated cells and productive replication or amplification is restricted to differentiated suprabasal cells. Amplification is dependent on the activation of the ATM DNA damage factors that are recruited to viral replication centers and inhibition of this pathway blocks productive replication. The STAT-5 protein appears to play a critical role in mediating activation of the ATM pathway in HPV-positive cells. While HPVs need to activate the DNA damage pathway for replication, cervical cancers contain many genomic alterations suggesting that this pathway is circumvented during progression to malignancy.

Keywords:

• amplification
• ATM
• CHK2
• differentiation
• DNA damage
• papillomaviruses
• replication foci
• STAT-5

Financial & competing interests disclosure

LA Laimins and S Hong were supported by grants from the NIH (R37 CA74202, RO1CA59655 and RO1CA142861). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Additional information

Funding

LA Laimins and S Hong were supported by grants from the NIH (R37 CA74202, RO1CA59655 and RO1CA142861). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript.