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Analysis of the mechanism by which telomerase impacts chromosomal stability and cell viability in Ku mutants
Author(s) -
Holland Cory Lee,
Lewis Lysle Kevin
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.22.1_supplement.596.2
Subject(s) - ku70 , ku80 , telomere , telomerase , genome instability , dna repair , microbiology and biotechnology , saccharomyces cerevisiae , polymerase , biology , mutant , dna , homologous recombination , protein subunit , dna damage , exonuclease , genetics , gene , dna binding protein , transcription factor
The Ku complex is a heterodimer comprised of two subunits, Ku70 and Ku80, which binds double‐stranded DNA (dsDNA) ends. Ku has multiple roles in DNA metabolism. The presence of Ku at the ends of the chromosomes protects the telomeres from degradation by nucleases and may also aid in recruitment of telomerase to DNA. Interestingly, Ku has also been shown to play a critical role in the non‐homologous end‐joining (NHEJ) pathway of repair of induced double‐strand breaks in DNA. In budding yeast ( Saccharomyces cerevisiae) , inactivation of either of the Ku subunit genes, YKU70 or YKU80 , abolishes NHEJ DNA repair and makes cells incapable of growing at elevated temperatures (37°C) due to telomere instability. The precise cause of telomere instability in yku70 mutants at high temperatures is unknown, but cell death can be alleviated by increasing levels of TLC1 , the RNA subunit of telomerase, as well as the polymerase subunit Est2. We have shown that overexpression of the Exo1 exonuclease accelerates the death of Ku mutants at 37°C and that TLC1 RNA and Est2 are able to rescue the accelerated death of Ku mutants. A series of yku70 double mutants that were constructed demonstrated that other telomere associated proteins such as Mlp2, Rif2, and Rad50 are not required for rescue. Funding for this project was provided in part by the Department of Chemistry and Biochemistry, Texas State University – San Marcos and Research Corporation.