The long-term goal of this project is to develop C. elegans as a model system for studying telomerase and telomere biology. Telomerase maintains chromosome integrity by adding de novo telomere repeats to chromosome termini. Most human somatic cells lack telomerase and display telomere erosion as they proliferate, which can lead to critical telomere shortening and senescence. We propose to study a promiscuous DNA replication process that may promote large-scale subtelomeric genome duplications at critically shortened telomeres. This process may be broadly relevant in genome evolution and could contribute to tumorigenesis. We hypothesize that telomere dysfunction can activate one or more stress response pathways that 1) may trigger systemic effects on organismal physiology that could contribute to aging or age-related diseases, 2) may promote survival in the absence of telomerase via a telomerase-independent telomere replication pathway termed Alternative Lengthening of Telomeres (ALT). A long-standing hypothesis in the field of chromosome biology is that aspects of genome evolution could be an orchestrated response to stress. The proposed studies will address this hypothesis in the context of telomere biology using a metazoan model system where a variety of conserved stress response pathways have been well characterized and where powerful genetic, cell biology and genomic tools are available: the nematode C. elegans. !

Public Health Relevance

Human somatic cells are deficient for telomerase and although telomere erosion can trigger senescence, the proposed studies will address a stress response pathway that is stimulated by telomere dysfunction and has systemic effects on physiology in the metazoan C. elegans, potentially revealing a central mechanism by which chromosome ends potentiate the aging process. We will also test the hypothesis that the activity of a stress response pathway promotes the telomerase- independent telomere maintenance mechanism ALT, which may occur in 10% of all human tumors and is not well understood. Finally, we address a promiscuous DNA replication process that may commonly occur during tumor development to create numerous genome rearrangements, some of which may be recurrent and could contribute to tumorigenesis.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM066228-11
Application #
8661189
Study Section
Cellular Mechanisms in Aging and Development Study Section (CMAD)
Program Officer
Carter, Anthony D
Project Start
2002-08-01
Project End
2017-05-31
Budget Start
2014-06-01
Budget End
2015-05-31
Support Year
11
Fiscal Year
2014
Total Cost
$329,771
Indirect Cost
$109,271
Name
University of North Carolina Chapel Hill
Department
Genetics
Type
Schools of Medicine
DUNS #
608195277
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599
Boerckel, Julie; Walker, Dana; Ahmed, Shawn (2007) The Caenorhabditis elegans Rad17 homolog HPR-17 is required for telomere replication. Genetics 176:703-9
Harris, Jasper; Lowden, Mia; Clejan, Iuval et al. (2006) Mutator phenotype of Caenorhabditis elegans DNA damage checkpoint mutants. Genetics 174:601-16
Clejan, Iuval; Boerckel, Julie; Ahmed, Shawn (2006) Developmental modulation of nonhomologous end joining in Caenorhabditis elegans. Genetics 173:1301-17
Meier, Bettina; Clejan, Iuval; Liu, Yan et al. (2006) trt-1 is the Caenorhabditis elegans catalytic subunit of telomerase. PLoS Genet 2:e18