Telomeres, the specialized protein-DNA structures present at the chromosomal terminus serve as 'caps' to prevent deleterious processes that would result in toss of linear chromosomes. The maintenance of an appropriate length of telomeric simple sequences to provide cap function is therefore essential for cell viability. Indeed, defects in telomere size control have been linked with both aging and oncogenesis. We have been studying the mechanism of size control in the yeast Saccharomyces cerevisiae as a model system. The basic outline of telomere size control is remarkably similar in yeast and vertebrates. Hence, the construction of a model system that can be easily manipulated gives us the opportunity to provide the framework for higher eukaryotic functional homologs. Previous studies have uncovered a process termed telomeric rapid deletion (TRD) that excises over-elongated telomere tracts to wild type sizes by a recombination mechanism. Two components regulate this process: the mechanism for the deletion process, and the mechanism of sizing among telomeres that governs the precision of deletion. The major goal in this proposal is to understand the mechanism of TRD.
Three aims will be pursued.
The first aim i s the characterization of the cell cycle control of TRD and the characterization of meiotic TRD which displays dramatically increased rates of TRD. The only protein known to be essential for TRD is the recombination protein Mre11.
The second aim i s to study the essential role of Mre11 in TRD through the extensive characterization of a battery of mis-sense alleles falling within unique domains of the protein The third aim examines an unusual allele of Mre11, A470T, that confers two major phenotypes, a loss of TRD precision and an ability to bypass senescence conferred by a loss of telomerase. Specific hypotheses f or the function of Mre11 in checkpoint control on telomere processing are tested using the tools made available from preliminary data. Proteins that interact with the motif surrounding A470T will be sought through the use of the Tap-tag method of isolating soluble native complexes. ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
1R01GM069943-01A1
Application #
6823434
Study Section
Cell Development and Function Integrated Review Group (CDF)
Program Officer
Carter, Anthony D
Project Start
2004-07-01
Project End
2008-06-30
Budget Start
2004-07-01
Budget End
2005-06-30
Support Year
1
Fiscal Year
2004
Total Cost
$271,755
Indirect Cost
Name
Tulane University
Department
Biochemistry
Type
Schools of Medicine
DUNS #
053785812
City
New Orleans
State
LA
Country
United States
Zip Code
70118
Lustig, Arthur J (2016) Hypothesis: Paralog Formation from Progenitor Proteins and Paralog Mutagenesis Spur the Rapid Evolution of Telomere Binding Proteins. Front Genet 7:10
Lustig, Arthur J (2015) Potential Risks in the Paradigm of Basic to Translational Research: A Critical Evaluation of qPCR Telomere Size Techniques. J Cancer Epidemiol Treat 1:28-37
Lustig, Arthur J; Sgura, Antonella (2013) A new era of allele-specific diagnostics? Front Genet 4:134
Joseph, Immanual S; Kumari, Alpana; Bhattacharyya, Mrinal K et al. (2010) An mre11 mutation that promotes telomere recombination and an efficient bypass of senescence. Genetics 185:761-70
Bhattacharyya, M K; Matthews, K M; Lustig, A J (2008) Mre11 nuclease and C-terminal tail-mediated DDR functions are required for initiating yeast telomere healing. Chromosoma 117:357-66
Bhattacharyya, Mrinal K; Lustig, Arthur J (2006) Telomere dynamics in genome stability. Trends Biochem Sci 31:114-22
Liaw, Hungjiun; Lustig, Arthur J (2006) Sir3 C-terminal domain involvement in the initiation and spreading of heterochromatin. Mol Cell Biol 26:7616-31
Williams, Bridget; Bhattacharyya, Mrinal K; Lustig, Arthur J (2005) Mre 11 p nuclease activity is dispensable for telomeric rapid deletion. DNA Repair (Amst) 4:994-1005
Joseph, Immanual; Jia, Dingwu; Lustig, Arthur J (2005) Ndj1p-dependent epigenetic resetting of telomere size in yeast meiosis. Curr Biol 15:231-7