Human telomeres (the structures that cap the ends of chromosomes) are composed of many kilobases of the repetitive sequence TTAGGG that together with telomere binding proteins prevent the cell from recognizing the ends as DNA breaks needing repair. Telomeres shorten due to incomplete DNA lagging strand synthesis/processing, and cellular senescence occurs when some have shortened sufficiently to induce a DNA damage signal. Cancer cells escape the proliferative limits of replicative aging by one of two mechanisms. Most frequently they up-regulate the expression of telomerase, an enzyme capable of adding telomere repeats to the ends of the chromosomes and maintaining their length. Much less frequently tumors activate a recombination-based ALT (Alternative Lengthening of Telomeres) mechanism for maintaining the ends of their chromosomes. The detailed structure of telomeres is very difficult to study because of the lack of restriction enzyme sites in the repetitive TTAGGG sequence (which prevents standard molecular biological approaches) and the fact that each diploid cell contains 92 telomeres (23 chromosomes x 2 ends x two copies of each). We have developed techniques that now permit us to address a large number of fundamental issues in telomere biology.
In Specific Aim 1, we will determine how rapidly following replication the mature structure of the 3'overhangs are established, what factors influence the timing or extent of this processing, when telomerase acts to elongate the G-strand, how much telomerase can add, how telomerase action and the C-strand fill-in are coordinated, and how special structures called t- loops are unfolded and reformed during replication.
Aim 2 explores the relationships between the mechanism that prevents restriction enzymes from digesting the region adjacent to the telomere and that which normally blocks recombination from occurring within the highly repetitive telomeric sequences. Investigations will include how these mechanisms are changed in cells using the ALT mechanism, and if many different types of ALT pathways exist. The results of these studies will not only advance our understanding of basic telomere regulation, but will also identify new therapeutic targets for inhibiting telomere maintenance in cancer (steps in telomerase elongation or ALT recombination) or slowing telomere shortening in age-related diseases. Project Narrative Telomeres cap the ends of all of our chromosomes and protect them from degradation. Telomere shortening causes replicative aging, and cancer cells are immortal because they acquire mechanisms to prevent this. Knowledge of the structure and processing of telomeres and the mechanisms by which they are maintained will provide targets for the development of new drugs to treat cancer and age-related diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG001228-33
Application #
8305530
Study Section
Cellular Mechanisms in Aging and Development Study Section (CMAD)
Program Officer
Guo, Max
Project Start
1992-01-15
Project End
2014-07-31
Budget Start
2012-08-01
Budget End
2014-07-31
Support Year
33
Fiscal Year
2012
Total Cost
$410,695
Indirect Cost
$149,105
Name
University of Texas Sw Medical Center Dallas
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
800771545
City
Dallas
State
TX
Country
United States
Zip Code
75390
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Lai, Tsung-Po; Zhang, Ning; Noh, Jungsik et al. (2017) A method for measuring the distribution of the shortest telomeres in cells and tissues. Nat Commun 8:1356
Min, Jaewon; Wright, Woodring E; Shay, Jerry W (2017) Alternative Lengthening of Telomeres Mediated by Mitotic DNA Synthesis Engages Break-Induced Replication Processes. Mol Cell Biol 37:
Opresko, Patricia L; Shay, Jerry W (2017) Telomere-associated aging disorders. Ageing Res Rev 33:52-66
Kim, Wanil; Shay, Jerry W (2017) Long-range telomere regulation of gene expression: Telomere looping and telomere position effect over long distances (TPE-OLD). Differentiation 99:1-9
Min, Jaewon; Wright, Woodring E; Shay, Jerry W (2017) Alternative lengthening of telomeres can be maintained by preferential elongation of lagging strands. Nucleic Acids Res 45:2615-2628
Jafri, Mohammad A; Ansari, Shakeel A; Alqahtani, Mohammed H et al. (2016) Roles of telomeres and telomerase in cancer, and advances in telomerase-targeted therapies. Genome Med 8:69
Sakellariou, Paraskevi; O'Neill, Andrea; Mueller, Amber L et al. (2016) Neuromuscular electrical stimulation promotes development in mice of mature human muscle from immortalized human myoblasts. Skelet Muscle 6:4
Min, Jaewon; Shay, Jerry W (2016) TERT Promoter Mutations Enhance Telomerase Activation by Long-Range Chromatin Interactions. Cancer Discov 6:1212-1214
Kim, Wanil; Ludlow, Andrew T; Min, Jaewon et al. (2016) Regulation of the Human Telomerase Gene TERT by Telomere Position Effect-Over Long Distances (TPE-OLD): Implications for Aging and Cancer. PLoS Biol 14:e2000016

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