Senior Scholar Award in Aging
Victoria Lundblad, Ph.D.
Baylor College of Medicine

Translating Yeast Telomere Biology to Human Cells: Identification of Activities that Regulate Human Telomere Maintenance and Cellular Proliferation

The telomeric caps at the ends of chromosomes are essential for maintaining the integrity of eukaryotic genomes. Two processes must be fully operational in order to prevent telomere dysfunction: chromosome ends need to be fully replicated and these termini also need to be protected from the activities that normally act on DNA strand breaks. The cell employs a number of different protein complexes to achieve these two functions. One of the most well-studied of these complexes is the enzyme telomerase, but recent years have uncovered additional proteins that regulate telomerase as well as other protein complexes that provide chromosome end protection.

Past research in the Lundblad laboratory has relied on baker’s yeast as an experimental system for the detailed analysis of mechanisms that maintain chromosome ends. This choice has stemmed from numerous observations indicating that there is an exceptionally high level of conservation between the telomere maintenance mechanisms used by human and model organisms. The unique DNA structure found at the end of the chromosome, the telomerase enzyme responsible for replicating telomeres, as well as essential telomere binding proteins, were all first identified in model organisms. In addition, the experimental paradigm for the relationship between telomere replication and cellular senescence was first established in yeast, and recapitulated in human cells several years ago.

During the past four years, Dr. Lundblad and her colleagues have made a number of key observations about the regulation of both telomere replication and telomere end protection in budding yeast. Dr. Lundblad now plans to extend these recent observations about yeast telomere biology to human cells. Specifically, she plans to investigate whether the same factors that regulate access of telomerase to yeast chromosome ends are also responsible for similar regulation in human cells. In addition, she plans to ask whether a protein complex responsible for end protection in yeast can be similarly identified in human cells.

Long term, information from such studies may be applied to our understanding of how telomere maintenance can contribute to the aging process. At the organismal level, defects in telomere function have already been demonstrated to have an impact on both longevity and age-related phenotypes. For example, the progeroid Werner’s syndrome shows defects in telomere length maintenance, and in mice, critical telomere shortening leads to a subset of age-dependent phenotypes, such as a reduced life span, impaired wound healing and hematopoietic ablation. This argues that future efforts to modulate aspects of human aging (such as improving an aging immune system) will rely – at least in part – on the ability to correct telomere length defects. However, it is unlikely that such efforts will solely depend on restoring the gene(s) responsible for telomerase activity. For example, telomeres continue to shorten in peripheral blood lymphocytes, despite the presence of telomerase activity. Thus, understanding the role of additional regulators of telomere function may be crucial to the eventual development of aging-specific therapeutic efforts directed at rescuing telomere maintenance defects.

Contact Dr. Lundblad.