Fully Funded Postdoctoral Position Working on Oncogenic Human Papillomaviruses
Human papillomaviruses (HPV) are the causative agents of cervical, anal and many oral cancers. In Western countries, the number of HPV-induced oropharnygeal cancers is increasing rapidly and deaths by these cancers will soon surpass those due to cervical cancer. While prophylactic vaccines to prevent initial HPV infection have been developed, there is no effective drug 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. A low level of viral gene expression is detected in infected basal cells and significant levels of viral transcripts are only seen in differentiated cells. Productive genome replication, late gene expression, and virion assembly are restricted to the nuclei of highly differentiated cells present in the uppermost epithelial layers. The goal of our studies is to understand how the HPV life cycle is regulated by DNA damage pathways, cellular transcription factors including epigenetic modifications and the innate immune response. My laboratory recently demonstrated that the amplification of viral genomes in differentiating cells is dependent on the constitutive activation of the ATM double strand DNA break repair pathway in HPV positive cells. Our studies have shown that this results from E7-induced activation of the innate immune transcription factor, STAT-5. STAT-5 also turns on the ATR single strand DNA damage repair pathway by directly increasing the expression of the replication/transcription factor TopBP1 that is a binding partner of ATR. For genome amplification to occur in suprabasal layers cells must retain the ability to re-enter S/G2 and our studies show that is dependent on p63 as well as the downstream transcriptional activator KLF4 that are controlled through HPV-induced post-translational effects. Another important regulator of the viral life cycle is the insulator factor CTCF which we have shown binds to sequences in the late regions of HPVs to regulate viral expression as well as replication through DNA looping to viral and cellular sequences. Finally, studies have shown that changes in the spectra of modified histones bound to viral genomes changes during the viral life cycle as well as upon progression to malignancy and helps regulate these activities.
Outline of projects available in the lab:
-mechanisms of activation of the DNA damage response by HPV E6 and E7
-role of epigenetic modifications to chromatin in regulating the HPV life cycle and progression to malignancy
-interplay of innate immune response and DNA damage pathways
-mechanisms of tumorigenesis in HPV positive oropharyngeal cancers