Our long-term goal is to understand the role of telomeres in aging and human disease. Telomeres are the specialized structure at both ends of each of our chromosomes that function to prevent the ends from being treated as broken DNA. If it were not for the capping function of telomeres, chromosomes would fuse together and tear themselves apart during cell division. The DNA replication apparatus cannot copy to the very end of our linear chromosomes, and a special enzyme called telomerase adds DNA to the ends to compensate for the shortening that would otherwise occur. Telomerase is expressed during early embryonic development (which permits telomere length to be maintained and our survival as a species) and in certain of our proliferative stem cells (where it slows but does not prevent telomere shortening from occurring to allow an increased number of cell divisions). Telomerase is turned off in most of our tissues, and the subsequent telomere shortening limits the number of times cells within these tissues can divide. This blocks most pre-malignant cells from acquiring the number of mutations they need to form tumors, but also limits cell turnover and almost certainly contributes to the physiological decline in some tissues associated with aging. Telomeres are much more difficult to study than a typical gene because we have 92 of them (one on each end of our 23 pairs of chromosomes), they are composed many kilobases of repetitive TTAGGG sequences that lack restriction sites, and their size is different for each chromosome end. We have developed a large number of novel techniques to study telomeres that permit us to address many important questions in our field. The present application develops new techniques and extends our current observations in two broad aims.
The first aim i s to open up an entire new field for the ways by which telomere shortening affects human biology. The field has focused its efforts on the consequences of replicative aging, which occurs when telomeres become so short they produce DNA damage signaling. Our preliminary data demonstrates different mechanisms by which telomere shortening can change the expression of subtelomeric genes throughout life, and one specific disease in which this occurs. We propose to identify many additional genes affected by telomere shortening and their consequences for human aging and disease.
Our second aim uses the techniques we have developed to analyze the many processing steps that occur when telomeres replicate, the nature of the structures that prevent the ends from being recognized as damaged DNA, and the nature of one mechanism by which tumor cells escape the barrier of replicative aging. The results of these studies are critical to understanding telomere behavior and for identifying targets for therapeutic interventions to counteract the effects of telomere shortening or treat the mechanisms by which tumor cells prevent telomere shortening.

Public Health Relevance

Telomeres, the structures that cap the ends of all of our chromosomes, shorten throughout life and have been shown to be critically important for the long-term division of cancer cells. Their role in human aging and disease remains much more speculative. This proposal will identify many of the genes and diseases that are affected by telomere shortening, will firmly establish that telomeres have a role in human aging, and will provide information necessary for developing therapeutics to manipulate telomere length and counteract these changes.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
2R01AG001228-34A1
Application #
8695883
Study Section
Cellular Mechanisms in Aging and Development Study Section (CMAD)
Program Officer
Guo, Max
Project Start
Project End
Budget Start
Budget End
Support Year
34
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Texas Sw Medical Center Dallas
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
City
Dallas
State
TX
Country
United States
Zip Code
75390
Lue, Neal F; Chan, Jamie; Wright, Woodring E et al. (2014) The CDC13-STN1-TEN1 complex stimulates Pol ? activity by promoting RNA priming and primase-to-polymerase switch. Nat Commun 5:5762
Ludlow, Andrew T; Robin, Jerome D; Sayed, Mohammed et al. (2014) Quantitative telomerase enzyme activity determination using droplet digital PCR with single cell resolution. Nucleic Acids Res 42:e104
Stadler, Guido; Rahimov, Fedik; King, Oliver D et al. (2013) Telomere position effect regulates DUX4 in human facioscapulohumeral muscular dystrophy. Nat Struct Mol Biol 20:671-8
Kim, Jinyong; Eskiocak, Ugur; Stadler, Guido et al. (2011) Short hairpin RNA screen indicates that Klotho beta/FGF19 protein overcomes stasis in human colonic epithelial cells. J Biol Chem 286:43294-300
Gomes, Nuno M V; Ryder, Oliver A; Houck, Marlys L et al. (2011) Comparative biology of mammalian telomeres: hypotheses on ancestral states and the roles of telomeres in longevity determination. Aging Cell 10:761-8
Tennen, Ruth I; Bua, Dennis J; Wright, Woodring E et al. (2011) SIRT6 is required for maintenance of telomere position effect in human cells. Nat Commun 2:433
Zhao, Yong; Abreu, Eladio; Kim, Jinyong et al. (2011) Processive and distributive extension of human telomeres by telomerase under homeostatic and nonequilibrium conditions. Mol Cell 42:297-307
Gomes, Nuno M V; Shay, Jerry W; Wright, Woodring E (2010) Telomere biology in Metazoa. FEBS Lett 584:3741-51
Zhao, Yong; Sfeir, Agnel J; Zou, Ying et al. (2009) Telomere extension occurs at most chromosome ends and is uncoupled from fill-in in human cancer cells. Cell 138:463-75
Zhao, Yong; Hoshiyama, Hirotoshi; Shay, Jerry W et al. (2008) Quantitative telomeric overhang determination using a double-strand specific nuclease. Nucleic Acids Res 36:e14

Showing the most recent 10 out of 45 publications