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Peter Tattersall, PhD
Professor of Laboratory Medicine and Genetics
Director of Graduate Studies in Microbiology

CB 408
203-785-4586
peter.tattersall@yale.edu

1968; B.Sc.; Univ of Glasgow, Scotland
1971; Ph.D.; Univ College, London, England
Fellowship: Roche Institute of Molecular Biology; Yale University

Community of Science Biosketch

Research Interests
Our research efforts are directed at understanding the molecular mechanisms by which mammalian parvoviruses target particular cell types, express their genes, take over their host cells and replicate their own DNA. The parvoviruses are relatively simple viruses, and we believe that understanding, and eventually controlling, their target cell specificity and cytotoxicity will to lead to their use as vectors for the expression of therapeutic genes in human cells, and to the exploitation of the viral non-structural gene products themselves as directed cancer cell death effectors.

We have cloned human cDNAs encoding the two subunits, p96 and p79, of parvoviral initiation factor (PIF) from HeLa cells. These are transcriptionally-active molecules which share about 40% overall protein identity, most apparent in a 93 amino acid domain carrying the KDWK motif characteristic of an emerging family of combinatorial transcription modulators, first recognized in studies of the Drosophila homeobox activator DEAF-1. Recently, PIF has been shown to be identical to the glucocorticoid modulatory element binding protein (GMEB), which binds to known regulatory elements in several host cell genes. We have shown that the genes encoding p96 and p79 are not linked in the human genome, but are located at chromosome 1p33 and 20qter, respectively, by radiation hybrid analysis, confirmed by FISH analysis. The genes encoding p96 and p79 span >41kb and >30 kb and contain 10 and 9 exons, respectively, separated by introns which appear to be unrelated, between the two genes, by size or sequence, implying that they have been apart for a significant evolutionary period. The region of homology between the two PIF/GMEB genes and other members of the KDWK family resides on three adjacent exons whose borders are completely conserved between the two PIF/GMEB genes.

The KDWK domain, carried on the central of these three exons, encodes the DNA binding specificity of the polypeptide. This activity is remarkable because the complex binds coordinately to two copies of the tetranucleotide RCGY, which can be spaced anywhere between one and fifteen nucleotides apart. Modified SELEX experiments indicate that the preferred half-site sequence is ACGT, and the optimal spacing between the two tetrads is five nucleotides, although half-sites spaced at 3, 4 and 6 nucleotides are selected with almost equivalent efficiency. Both p96 and p79 polypeptides are able to self dimerize and both homodimers bind similar optimally configured sequence arrangements with slightly different optimal tetrad sequences, though still conforming to the RCGY consensus. This suggests that the subunits of PIF may be part of a combinatorial transcription factor system for the fine control of differential gene expression in metazoans.

We have also continued to develop improved parvoviral vectors. We have constructed a series of vectors based on the lymphotropic strain of MVM for the transduction of transgenes into both murine and human T cells. These vectors incorporate features which are designed to suppress the production of replication-competent virus (RCV). Extensive testing with sensitive assays, including low dilution blind passage in permissive cells and Southern blots of inoculated monolayers, indicate that vectors containing even a short overlap of homology with their helper plasmid at the C-terminus of the VP genes generate detectable RCV, while those in which the overlap is eliminated do not, allowing us to produce RCV-free vector virus stocks with titers sufficient to conduct animal experiments. Vectors have now been constructed on this backbone that transduce the murine immunomodulatory molecule B7.1 into target cells and we are currently assessing the efficacy of these vectors in a tumor suppression model based on the EL4 lymphoma transplanted into C57/Bl6 mice.

Publications

Cotmore, S.F., Gottlieb R.L. and Tattersall, P.  Replication initiator protein NS1 of parvovirus MVM binds to modular divergent sites distributed throughout duplex viral DNA.  J. Virol. In press, 2007.

Cotmore, S.F. and Tattersall, P.  Parvoviral host range and cell entry mechanisms.  Advances in Virus Research, 70, Ch 5, 183-232, 2007

Paglino, J., Burnett, E., & Tattersall, P.  Exploring the contribution of distal P4 promoter elements to the oncoselectivity of Minute Virus of Mice.  Virology, in press, 2007.

Burnett, E., Cotmore, S.F., & Tattersall, P.  Segregation of a single outboard left-end origin is essential for the viability of parvovirus Minute Virus of Mice.  J. Virol., 80:10879-83, 2006.

Ruiz, Z., D'Abramo, A.M. Jr., & Tattersall, P.  An essential role for the C-terminal hexapeptide domain of the NS2P splice variant during MVM infection of murine cells.   Virology, 349:382–395, 2006.

Farr, G., Cotmore, S.F. & Tattersall, P.  VP2 cleavage and a leucine ring at the base of the five-fold cylinder control pH-dependent externalization of both the VP1 N-terminus and the genome of Minute Virus of Mice.  J. Virol., 80:161–171, 2006.

Cotmore S.F. & Tattersall P. Parvoviruses. Chapter 29 in "DNA replication and Human Disease".  DePamphilis M., ed. Cold Spring Harbor Laboratory Press.  Cold Spring Harbor, New York. pp 593-608, 2006.

Tattersall, P.   The evolution of parvoviral taxonomy.  Chapter 1, in "The Parvoviruses", Kerr, J., Cotmore, S.F., Bloom, M.E., Linden, R.M., & Parrish, C.R., eds., Hodder Arnold, London, pp. 5-14, 2006.

Cotmore S.F. & Tattersall P.  Genome Structure and Organization.  Chapter 7 in “Parvoviruses.” Kerr, J.R., Cotmore, S.F., Bloom, M.E., Linden, R.M., & Parrish, C.R. eds.  Edward Arnold Ltd., London, pp 73-94, 2006.

Cotmore, S. F. & Tattersall, P.   A rolling hairpin strategy: basic mechanisms of DNA replication in the parvoviruses. Chapter 14, in "The Parvoviruses", Kerr, J., Cotmore, S.F., Bloom, M.E., Linden, R.M., & Parrish, C.R., eds., Hodder Arnold, London, pp. 171-188, 2006.

Farr, G., Zhang, L-G., & Tattersall, P.  Parvoviral virions deploy a capsid-tethered lipolytic enzyme to breach the endosomal membrane during cell entry. Proc. Natl. Acad. Sci. U.S.A., 102:17148–53, 2005.

D’Abramo Jr., A. M., Ali, A. A., Wang, F., Cotmore, S.F. & Tattersall, P.  Host range mutants of Minute Virus of Mice with a single VP2 amino acid change require additional silent mutations that regulate NS2 accumulation.  Virology, 340:143-154, 2005.

Wollmann, G., Tattersall, P., & van den Pol, A.N.  Targeting human glioblastoma cells - comparison of nine viruses with oncolytic potential. J. Virol., 79:6005-22, 2005.

Cotmore, S. F. & Tattersall, P.  Encapsidation of Minute Virus of Mice DNA: aspects of the translocation mechanism revealed by the structure of partially-packaged genomes. Virology, 336:100-112, 2005.

Cotmore, S. F. & Tattersall, P.  Packaging sense is controlled by the efficiency of the nick site in the right-end replication origin of parvoviruses MVM and LuIII.  J. Virol., 79:2287-300, 2005.

Tattersall, P. & Cotmore, S. F. The Parvoviruses.   Chapter 21 in Topley and Wilson's Microbiology and Microbial Infections. 10th edition - Virology, Vol I, Mahy, B.W.J. & ter Meulen, V., eds., Hodder Arnold, London, pp.  407-438, 2005.

Tattersall, P., Bergoin, M., Bloom, M. E., Brown, K. E., Linden, R. M., Muzyczka, N., Parrish, C. R., & Tijssen, P.   Parvoviridae. In "Virus Taxonomy, VIIIth Report of the ICTV" (C. M. Fauquet, M. A. Mayo, J. Maniloff, U. Desselberger, & L. A. Ball, Eds.). Elsevier/Academic Press, London, 2005.