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Alison McBride, Ph.D.
Building 33, Room 3W20B.4
33 North Drive
Bethesda, MD 20892-3203
Phone: 301-496-1370
Fax: 301-451-5330
amcbride@nih.gov

Laboratory of Viral Diseases

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Alison McBride, Ph.D.

Photo of Alison McBride, Ph.D.

Chief, DNA Tumor Virus Section, LVD

Major Areas of Research

  • Characterization of the mechanisms of viral genome establishment in keratinocytes
  • Characterization of the mechanisms by which papillomavirus genomes are maintained and partitioned in dividing cells
  • Determination of the role of the host DNA damage response and repair pathways in viral DNA replication
  • Development of therapeutics to intervene in viral genome tethering
  • Development of efficient methods to conditionally immortalize primary keratinocytes
 

Program Description

Papillomaviruses are small DNA viruses that persistently infect and replicate in stratified cutaneous and mucosal epithelia. Each papillomavirus type is species-specific and has a tropism for certain types of epithelia. In most cases, the resulting papillomas are benign, but infection with certain papillomavirus types can lead to the development of carcinomas.

The papillomavirus lifecycle. Credit: NIAID
The papillomavirus lifecycle. Credit : NIAID

The basal cells of stratified epithelia constantly divide to replenish the overlying differentiated cell layers. The viral DNA replicates and is maintained in these dividing basal cells as low copy, extrachromosomal circular DNA molecules. Viral genome amplification and synthesis of capsid proteins occurs only in the upper layers of the epithelium. Papillomavirus infections are usually long-lived, and the dividing basal cells provide a reservoir of infected cells for the overlying virus producing tissue. This strategy requires that the papillomaviruses have a faithful and robust mechanism to replicate and retain their extrachromosomal genomes in the nuclei of dividing cells.

Papillomaviruses have exploited interactions between virus and host chromatin at many stages of the viral life cycle. Viral DNA is targeted to beneficial regions of the host nucleus to ensure that the genomes are transcriptionally active and are not eliminated from the cell or repressed in heterochromatin. Viral genomes are tethered to specific regions of host mitotic chromosomes to efficiently partition the viral genomes to daughter cells. Viral DNA replication also initiates at specific regions of host chromatin, where the viral E1 and E2 proteins initiate a DNA damage response that recruits cellular DNA repair proteins to viral replication foci for efficient viral DNA synthesis.

BPV-1 E2-mediated viral genome partitioning. Credit: NIAID.
BPV-1 E2-mediated viral genome partitioning. Credit: NIAID

The papillomavirus genomes are tethered to host chromatin by the viral E2 protein. The E2 protein binds specifically to repeated DNA binding motifs in the viral genomes and links them to the host chromosomes via protein-protein interactions. This ensures that viral genomes remain in the nucleus and are partitioned to daughter cells in approximately equal numbers. There are variations in the association of different papillomavirus E2 proteins with mitotic chromosomes, and different papillomaviruses have evolved to bind to different chromosomal targets to partition their genomes. Other persistent DNA viruses, such as the gamma herpesviruses, have adopted a similar strategy to retain and partition their genomes in dividing cells.

Variations in E2 binding patterns on mitotic chromosomes. E2 (green); spindle (red); mitotic chromosomes (blue). The HPV11 pattern was observed after prepermeabilization. Credit: NIAID.
Variations in E2 binding patterns on mitotic chromosomes. E2 (green); spindle (red); mitotic chromosomes (blue). The HPV11 pattern was observed after prepermeabilization. Credit: NIAID

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Biography

Dr. McBride received a B.Sc.(with Honors) in molecular biology from the University of Glasgow, Scotland, and a Ph.D. in biochemistry from the Imperial Cancer Research Fund and Imperial College, London, studying Epstein-Barr virus. She began working on human and other papillomaviruses as a postdoctoral fellow in the National Cancer Institute and joined NIAID in 1994. She became a senior investigator in the Laboratory of Viral Diseases in 2000.

Research Group

Moon-Kyoo Jang, Staff Scientist
Nozomi Sakakibara, Postdoctoral Fellow
Jameela Khan, Postdoctoral Fellow
Koenraad van Doorslaer, Postdoctoral Fellow
Wesley Stepp, Predoctoral Fellow

Selected Publications

McBride AA, Sakakibara N, Stepp WH, Jang MK. Hitchhiking on host chromatin: how papillomaviruses persist. Biochim Biophys Acta. 2012 Jul;1819(7):820-5.

Liu X, Ory V, Chapman S, Yuan H, Albanese C, Kallakury B, Timofeeva OA, Nealon C, Dakic A, Simic V, Haddad BR, Rhim JS, Dritschilo A, Riegel A, McBride A, Schlegel R. ROCK inhibitor and feeder cells induce the conditional reprogramming of epithelial cells. Am J Pathol. 2012 Feb;180(2):599-607.

Sakakibara N, Mitra R, McBride AA. The papillomavirus E1 helicase activates a cellular DNA damage response in viral replication foci. J Virol. 2011 85:8981-95.

Chapman S, Liu X, Meyers C, Schlegel R, McBride AA. Human keratinocytes are efficiently immortalized by a Rho kinase inhibitor. J Clin Invest. 2010 120:2619-26.

Sekhar V, Reed SC, McBride AA. Interaction of the betapapillomavirus E2 tethering protein with mitotic chromosomes. J Virol. 2010 84:543-57.

Jang MK, Kwon D, McBride AA. Papillomavirus E2 proteins and the host BRD4 protein associate with transcriptionally active cellular chromatin. J Virol. 2009 83:2592-600.

Visit PubMed for a complete publication listing.

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PaVE

The PapillomaVirus Episteme: An HPV Sequence Database

In collaboration with the NIAID Office of Cyber Infrastructure and Computational Biology Bioinformatics and the Computational Biosciences Branch, we established the PapillomaVirus Episteme (PaVE) to provide information and bioinformatics resources to the scientific community for research on the Papillomaviridae. The goal of PaVE is to provide an HPV sequence database and tools that will accelerate scientific progress and ultimately our understanding, detection, diagnosis, and treatment of diseases caused by papillomaviruses. Find out more about the PaVE animal papillomavirus and human papillomavirus (HPV) sequence database.

Last Updated September 12, 2012

Last Reviewed September 12, 2012