Telomerase and telomere length has been implicated in the human conditions of cancer and ageing. A genetic approach has been used to identify four proteins required for telomerase activity in yeast, but only one of these proteins has any clear homologs in higher eukaryotes. C. elegans is a multicellular eukaryote in which telomerase can be studied using an unbiased forward genetic approach. Thus far, one C. elegans gene that is required for telomerase activity, mrt-2, has been identified, and MRT-2 is a DNA damage checkpoint protein.
The specific aims of this proposal are: 1. To show that the mrt-3 mutant is defective for the C. elegans catalytic subunit of telomerase. 2. To map another C. elegans telomerase mutant, mrt-1, at high resolution, to clone mrt-1, and to determine the function of mrt-1. 3. To conduct a large-scale genetic screen in an attempt to identify most or all C. elegans genes that are required for telomerase activity. To map the positions of these mutants, and to test for complementation between mutants whose map positions are close together. Some of these genes will then be mapped at high resolution and cloned. Possible functions of these genes that are required for telomerase activity in vivo will be assessed using a combination of genetic, phenotypic and biochemical studies. These experiments, which use the power of C. elegans genetics to study how telomeres of higher eukaryotes are replicated, should complement biochemical and reverse genetic approaches that are currently being used in other organisms.
|Shtessel, Ludmila; Lowden, Mia Rochelle; Cheng, Chen et al. (2013) Caenorhabditis elegans POT-1 and POT-2 repress telomere maintenance pathways. G3 (Bethesda) 3:305-13|
|Cheng, Chen; Shtessel, Ludmila; Brady, Megan M et al. (2012) Caenorhabditis elegans POT-2 telomere protein represses a mode of alternative lengthening of telomeres with normal telomere lengths. Proc Natl Acad Sci U S A 109:7805-10|
|Shtessel, Ludmila; Ahmed, Shawn (2011) Telomere dysfunction in human bone marrow failure syndromes. Nucleus 2:24-9|
|Lowden, Mia Rochelle; Flibotte, Stephane; Moerman, Donald G et al. (2011) DNA synthesis generates terminal duplications that seal end-to-end chromosome fusions. Science 332:468-71|
|Bailly, Aymeric P; Freeman, Alasdair; Hall, Julie et al. (2010) The Caenorhabditis elegans homolog of Gen1/Yen1 resolvases links DNA damage signaling to DNA double-strand break repair. PLoS Genet 6:e1001025|
|Meier, Bettina; Barber, Louise J; Liu, Yan et al. (2009) The MRT-1 nuclease is required for DNA crosslink repair and telomerase activity in vivo in Caenorhabditis elegans. EMBO J 28:3549-63|
|Boerckel, Julie; Walker, Dana; Ahmed, Shawn (2007) The Caenorhabditis elegans Rad17 homolog HPR-17 is required for telomere replication. Genetics 176:703-9|
|Meier, Bettina; Clejan, Iuval; Liu, Yan et al. (2006) trt-1 is the Caenorhabditis elegans catalytic subunit of telomerase. PLoS Genet 2:e18|
|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|