HPV and the DNA Damage Response

Project: Research project

Project Details


Human papillomaviruses (HPV) are the causative agents of cervical, anal and many oral cancers. While
prophylactic vaccines to prevent HPV infections have been developed, there is no effective therapeutic
treatment for existing HPV lesions. It is therefore of critical importance to understand how the productive life
cycle of high-risk HPVs is regulated to identify potential new therapeutic targets. HPVs infect stratified
squamous epithelia and link their productive life cycles to the differentiation of the infected cell. My laboratory
recently demonstrated that the amplification of HPV genomes in differentiating cells is dependent on activation
of the ataxia-telangiectasia mutated (ATM) kinase pathway. In contrast, the ATM pathway has minimal effects
on stable maintenance replication in undifferentiated cells. In HPV positive cells, members of the ATM
pathway, such as γ−H2AX, CHK2, and NBS1, are bound to viral genomes in distinct nuclear replication foci.
Our studies have shown that E7 and E1 can activate the DNA damage response in the absence of viral
genome replication and that they act through the innate immune regulator, STAT-5 and Tip60 to induce the
phosphorylation of ATM. Additional studies using complete viral genomes have indicate that additional viral
proteins, such as E5, can also activate the DNA damage pathways. Our experiments specifically implicate
homologous recombination factors in mediating HPV amplification. In addition to the ATM pathway, we recently
found that both the ataxia telangiectasia and Rad3-related (ATR) pathway, which is important for repair of
single strand breaks, along with the p38/MK2 factors are also critical for amplification.. Additional recent
studies demonstrate that the cohesin, SMC1, is activated in HPV positive cells as part of the DNA damage
response and that it forms complexes with the transcriptional insulator, CTCF, at specific sites on HPV
genomes. Knockdown of either SMC1 or CTCF blocks differentiation-dependent HPV genome amplification
and mutation of SMC1/CTCF binding sites in HPV 31 interferes with stable maintenance of viral episomes.
While we have identified members of the DNA damage pathways that are important for differentiation
dependent amplification, the mechanism by which they act is still unclear and investigating this is a major focus
of this renewal application. The overall goal of our studies is to understand how members of the DNA damage
pathways regulate the differentiation-dependent HPV life cycle. We will address the following questions: 1).
How do ATM and ATR regulate HPV genome amplification? Are double strand breaks introduced into HPV
genomes? 2). How does the p38/MK2 pathway contribute to amplification? 3). What is the mechanism by
which HPV proteins initiate the DNA damage response?
Effective start/end date7/1/166/30/21


  • National Cancer Institute (5R01CA142861-10)


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