The work in our laboratory focuses on the pathogenesis of human papillomaviruses (HPV); small DNA viruses that exhibit epithelial tropism. Of the over 100 types of HPV identified, fifteen of these are categorized as high-risk and are considered the causative agents of cervical cancer. High-risk HPVs are also associated with cancers of the anus, oropharynx and esophagus, identifying HPV as a risk factor for multiple human cancers. The life cycle of HPV is dependent on cellular factors and epithelial differentiation. Differentiation triggers the productive phase of the life cycle, which includes viral genome amplification, late gene expression and virion production. Paradoxically, these events occur in differentiated cells that normally would have exited the cell cycle. To ensure virion production, HPV proteins re-program the cellular DNA synthesis machinery upon differentiation, pushing cells into S phase to allow for viral replication. The ability of the HPV oncoproteins E6 and E7 to target critical regulators of cell cycle progression results in the bypass of checkpoints that would normally eliminate abnormal cells. This results in the accumulation of genetic alterations that eventually lead to transformation and cancer development. However, the mechanisms by which the differentiation-dependent phase of the viral life cycle is regulated are unclear. My lab is interested in defining signaling pathways modulated by HPV that promote the productive phase of the life cycle, in turn contributing to viral pathogenesis and possibly transformation.
- What is the role of the cellular DNA damage response in the viral life cycle? We have found that high-risk HPVs utilize DNA repair pathways for productive viral replication in differentiating epithelial cells. We are interested in determining how HPV proteins activate and utilize DNA damage response (DDR) pathways to promote viral replication, as well as understanding the impact of DDR activation on genomic stability and the development of HPV-associated cancers.
- How is the viral life cycle epigenetically regulated? HPV genomes are histone associated in the virion as well as in infected cells, adopting a nucleosome pattern similar to that found in cellular DNA. We have found that certain histone post-translational modifications are required for HPV replication. We are interested in understanding how these epigenetic modifications on cellular, as well as viral DNA support HPV replication, and in turn, viral persistence. Identifying epigenetic modifiers and modifications that are required for viral replication may allow for the development of novel therapeutics to treat HPV-associated infections and malignancies.
Sitz, J., Blanchet, S.A., Gameiro, S.F., Biquand, E., Morgan T.M., Lavoie, E.G., Blondeau, A., Smith, B.C., Mymryk, J.S, Moody, C.A., Fradet-Turcotte, A. 2019. Human papillomavirus E7 oncoprotein targets RNF168 to hijack the host DNA damage Response. PNAS. 2019 Sep 24;116(39):19552-19562.
Gautam, D., Johnson, B.A., Mac, M., Moody, C.A. SETD2-dependent H3K36me3 plays a critical role in epigenetic regulation of the HPV31 life cycle. 2018. PLoS Pathogens. Oct 12;14(10):e1007367.
Hopcraft, S.E., Moody, C.A., Damania, B. 2018. Air-Liquid Interface System To Understand Epstein-Barr Virus-Associated Nasopharyngeal Carcinoma. mSphere. July 18;3(4).
Moody, C.A. 2017. Mechanisms by Which HPV Induces a Replication Competent Environment in Differentiating Keratinocytes. Viruses. Sep 19;9(9). pii: E261. doi: 10.3390/v909026
Anacker, D.A., and Moody, C.A. 2017. Modulation of the DNA Damage Response During the Life Cycle of Human Papillomaviruses. Virus Research. March 2; 2;231:41-49 .
Johnson, B.A., Aloor, H.L., Moody, C.A. 2016. The Rb Binding Domain of HPV31 E7 is Required for Maintenance of High Levels of DNA Repair Factors. Virology. Oct 19;500:22-34.
Anacker, D.A., Aloor, H.L., Shepard, C.N., Lenzi, G.M, Kim, B., Moody, C.A. 2016. HPV31 Utilizes the ATR-Chk1 Pathway to Maintain Elevated RRM2 Levels and a Replication-Competent Environment in Differentiating Cells. Virology. Dec; 499:383-396. Chosen as a highlighted article for the December issue.
Gautam, D and Moody, C.A. 2016. Impact of the DNA Damage Response on Human Papillomavirus Chromatin. PLoS Pathogens. Jun 16;12(6):e1005613. doi: 10.1371/journal.ppat.1005613.
Chapell, W.H., Gautam, D., Ok, S.T., Johnson, B.A., Anacker, D.A., Moody, C.A. 2016. Homologous Recombination Factors, Rad51 and BRCA1, are Required for Productive Replication of Human Papillomavirus 31. J. Virol. March; 90(5):2639-2652.
Bentz, G.L., Moss, C.R. 2nd, Whitehurst, C.B., Moody, C.A., Pagano, J.S. 2015. LMP1-induced Sumoylation Influences the Maintenance of EBV Latency Through KAP1. J. Virol. Aug: 89(15): 7465-7477.
Anacker, D.C., Gautam, D., Gillespie, K.A., Chappell, W.H., Moody, C.A. 2014. Productive Replication of Human Papillomavirus 31 Requires the DNA Repair Factor Nbs1. J. Virol. Aug: 88(15): 8528-8544.
Gillespie, K.A., Mehta, K.P., Laimins L.A, Moody, C.A. 2012. Human Papillomaviruses Recruit Cellular DNA Repair and Homologous Recombination Factors to Viral Replication Centers. J Virol. Sep: 86(17): 9520-9526.
Anacker, D. and Moody, C. 2012. Generation of Organotypic Raft Cultures from Primary Human Keratinocytes. J Vis Exp. Feb 22;(60). pii: 3668. doi: 10.3791/3668.
Fradet-Turcotte A., Bergeron-Labrecque F., Moody C.A., Lehoux M., Laimins L., Archambault J. 2011. Nuclear Accumulation of the Papillomavirus E1 Helicase Blocks S-Phase Progression and Triggers an ATM-Dependent DNA Damage Response. J Virol. 85(17): 8996-9012.
Knight GL, Pugh AG, Yates E, Bell I, Wilson R, Moody C.A., Laimins LA, Roberts S. 2011. A Cyclin-Binding Motif in Human Papillomavirus Type 18 (HPV18) E1^E4 is Necessary for Association with CDK-Cyclin Complexes, but is Not Required for Differentiation-Dependent Viral Genome Amplification or L1 Caspid Protein Expression. Virology. Mar 30;412(1):196-210.
Fradet-Turcotte A., Moody C.A., Laimins L.A., and J. Archambault. 2010. Nuclear Export of Human Papillomavirus type 31 E1 is Regulated by Cdk2 Phosphorylation and Required for Viral Genome Maintenance. J Virol. 84(22): 11747-11760.
Moody, C.A. and Laimins, L.A. 2010. Human Papillomavirus Oncoproteins: Pathways to Transformation. Nat Rev Cancer. 10(8):550
Moody, C.A. and L.A. Laimins. 2009. Human Papillomaviruses Activate the ATM DNA Damage Pathway for Viral Genome Amplification Upon Differentiation. PLoS Pathogens. 5(10), p.e1000605