Chromosomes are capped by structures called telomeres. DNA polymerase is unable to replicate the ends of linear DNA molecules, and the ribonucleoprotein telomerase compensates for this by adding telomeric repeats to the ends of the chromosome. Telomerase is turned off in most somatic tissues during development, and in its absence telomeres shorten. This ultimately limits the number of times normal human cells are able to divide. Cancer cells require 4-6 mutations to become malignant. Each mutation uses up 20-40 doublings, so limiting the available divisions functions as an antitumor mechanism by preventing premalignant cells that have accumulated one or two mutations from dividing. Immortalization occurs when cells activate telomere-maintenance mechanisms, usually following the derepression of telomerase but sometimes via a telomerase-negative pathway that may involve recombination of telomeres. 85% of all cancer cells express telomerase activity, and inhibiting its activity is being tested for the treatment of malignancies. The recent ability to prevent telomere shortening by constitutively expressing the catalytic subunit of telomerase in normal diploid cells and the demonstration that this immortalizes the cells profoundly effects our approaches for the treatments of genetic defects, diseases of aging and cancer. In collaboration with Dr. Jerry Shay, my lab is exploring the structure of telomeres, the regulation of telomere positional effects, the role of telomerase in cancer, and the use of immortalized normal diploid cells for therapeutic purposes.
RESEARCH INTERESTS
Biology of aging and cancer
Telomeres and telomerase
Cell and molecular analysis of muscle cell differentiation
RECENT PUBLICATIONS
Shay, J.W. and W.E. Wright, "Hallmarks of telomeres in ageing research" J Pathology, 211:114-123, 2007
Chai, W., A. J. Sfeir, H. Hoshiyama, J. W. Shay and W. E. Wright, "The involvement of the Mre11/Rad50/Nbs1 complex in the generation of G-overhangs at human telomeres" EMBO Rep, 7:225-230, 2006
Chai, W., Q. Du, J. W. Shay and W. E. Wright, "Human telomeres have different overhang sizes at leading versus lagging strands" Mol Cell, 21:427-435, 2006
Wright, W. E., and Shay, J. W., "Telomere-binding factors and general DNA repair" Nat Genet, 17:116-118, 2005
Bechter, O. E., Y. Zou, J. W. Shay and W. E. Wright, "Homologous recombination in human telomerase-positive and ALT cells occurs with the same frequency" EMBO Rep, 4(12):1138-1143, 2003
SIGNIFICANT PUBLICATIONS
Sfeir, A. J., Chai, W., Shay, J. W., and Wright, W. E., "Telomere-end processing: the terminal nucleotides of human chromosomes." Mol Cell, 18:131-138, 2005
Steinert, S., J. W. Shay and W. E. Wright, "Modification of Subtelomeric DNA" Mol Cell Biol, 24(10):4571-4580, 2004
Baur, J.A., Y. Zou, J.W. Shay, and W.E. Wright, "Telomere position effect in human cells." Science, 292/5524:2075-2077, 2001
Herbert, B., A.E. Pitts, S.I. Baker, S.E. Hamilton, W.E. Wright, J.W. Shay, and D.R. Corey, "Inhibition of human telomerase in immortal human cells leads to progressive telomere shortening and cell death." Proc Natl Acad Sci U S A, 96/25:14276-14281, 1999
Bodnar, A.G., M. Ouellette, M. Frolkis, S.E. Holt, C.P. Chiu, G.B. Morin, C.B. Harley, J.W. Shay, S. Lichtsteiner, and W.E. Wright, "Extension of life-span by introduction of telomerase into normal human cells." Science, 279/5349:349-352, 1998
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