Alison McBride, Ph.D.

Chief, DNA Tumor Virus Section

Senior Investigator

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 HPV 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.

Description of Research Program

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 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, extra
chromosomal 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.

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

The extrachromosomal papillomavirus genomes are maintained and partitioned 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 mitotic chromosomes via a protein-protein interaction. This ensures that viral genomes remain in the nucleus and are segregated to daughter cells in approximately equal numbers. Other persistent DNA viruses,such as the gamma herpesviruses, have adopted a similar strategy to retain and partition their genomes in dividing cells.

This mechanism has been best studied for the bovine papillomavirus, BPV-1, and at least one host chromosomal target has been well characterized. However, 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.

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

The research mission of the DNA Tumor Virus Section is to do the following:

• Characterize the mechanism of replication and partitioning for different papillomaviruses.
• Identify and characterize the chromosomal targets for different papillomaviruses.
• Identify cis-elements in papillomavirus genomes that are essential for genome maintenance.
• Understand how papillomavirus genome replication and partitioning are regulated.
• Develop techniques to visualize and track viral DNA and protein in living cells.
• Develop therapeutics to intervene in viral genome tethering.
• Develop extrachromosomal papillomavirus vectors.

Research Group Members

Moon-Kyoo Jang, Staff Scientist; Atasi Poddar, Postdoctoral Fellow; Vera Stupina, Postdoctoral Fellow; Vandana Sekhar, Predoctoral Fellow; Sandra Dunn, Predoctoral Fellow

Selected Publications

(View list in PubMed.)

McBride AA. Replication and partitioning of papillomavirus genomes. Adv Virus Res. 2008;72:155-205.

Cardenas-Mora J, Spindler JE, Jang MK, McBride AA. Dimerization of the papillomavirus E2 protein is required for efficient mitotic chromosome association and Brd4 binding. J Virol.2008 Aug;82(15):7298-305.

McPhillips MG, Oliveira JG, Spindler JE, Mitra R, McBride AA. Brd4 is required for E2-mediated transcriptional activation but not genome partitioning of all papillomaviruses. J Virol. 2006 Oct;80(19):9530-43.

McBride AA, Oliveira JG, McPhillips MG. Partitioning viral genomes in mitosis: same idea, different targets. Cell Cycle. 2006 Jul;5(14):1499-502.

Soeda E, Ferran MC, Baker CC, McBride AA. Repression of HPV16 early region transcription by the E2 protein. Virology. 2006 Jul 20;351(1):29-41.

Oliveira JG, Colf LA, McBride AA. Variations in the association of papillomavirus E2 proteins with mitotic chromosomes. Proc Natl Acad Sci U S A. 2006 Jan 24;103(4):1047-52.

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