"Genetic analysis of the human disease-causing gene ATM in yeast Tel1 and Mec1 mutants"
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Ataxia-telangiectasia (A-T) is a recessive human disorder characterized by hypersensitivity to radiation, elevated risk of cancer development, nervous degeneration, premature senescence, and immune deficiencies. A-T is caused by mutation of the ATM gene located on human chromosome 11. The large protein product of ATM is a member of the phosphatidylinositol-3-kinase (PI3K) protein family. PI3K's are important for cellular response to DNA damage and are involved in DNA repair, genetic recombination, apoptosis, and cell cycle regulation. Human protein ATR and yeast proteins Mec1 and Tel1 are also PI3K's. Yeast tel1 mutants display chromosome instability and telomere shortening, and yeast mec1 mutants display sensitivity to DNA damaging agents, checkpoint misregulation, chromosome loss, and chromosome rearrangement. The defects observed in human cancer cells are similar to those observed in yeast mec1 and tel1 mutants. Previous research has shown that the human ATR protein can functionally complement the radiation sensitivity of a yeast mec1 mutant. Similarly, yeast tel1 p can partially functionally complement the human A-T phenotype, reducing recombination, apoptosis, and telomere shortening in A-T cells. However, Tel1 p does not reverse the A-T defects in cell cycle checkpoints and sensitivity to radiation, suggesting that these two processes may be regulated by Mec1 p. To determine whether the human ATM gene can functionally complement mec1 and tel1 in yeast, the full length ATM gene and ATM PI3K domain are being cloned and tested for functional complementation of tel1 and mec1 defects.
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