TEL1, an S. cerevisiae homolog of the human gene mutated in ataxia telangiectasia, is functionally related to the yeast checkpoint gene MEC1

Abstract

Patients with the genetic disorder ataxia telangiectasia (AT) have mutations in the AT mutated (ATM) gene, which is homologous to TEL1 and the checkpoint gene MEC1. A tel1 deletion mutant, unlike a mec1 deletion, is viable and does not exhibit increased sensitivity to DNA-damaging agents. However, increased dosage of TEL1 rescues sensitivity of a mec1 mutant, mec1-1, to DNA-damaging agents and rescues viability of a mec1 disruption. mec1-1 tel1 delta 1 double mutants are synergistically sensitive to DNA-damaging agents, including radiomimetic drugs. These data indicate that TEL1 and MEC1 are functionally related and that functions of the ATM gene are apparently divided between at least two S. cerevisiae homologs.

The role of ATM in DNA damage responses and cancer

“…Structural and functional homologs of MEC1 include the Drosophila melanogaster Mei-41 protein, the S. Pombe Rad3 protein, and the mammalian AT-and Rad3-related ATR/FRP1 protein (Hari et al, 1995;Bentley et al, 1996;Cimprich et al, 1996). The closest homolog to ATM in sequence similarity is the S. cerevisiae TEL1 gene product, deletions of which results in the shortening of telomeres (Morrow et al, 1995;Greenwell et al, 1995). Although TEL1 does not appear to play a major role in checkpoint function or viability, overexpression of TEL1 in a MEC1 mutant can rescue from cell death suggesting some functional redundancies between these two family members (Morrow et al, 1995).…”

“…The closest homolog to ATM in sequence similarity is the S. cerevisiae TEL1 gene product, deletions of which results in the shortening of telomeres (Morrow et al, 1995;Greenwell et al, 1995). Although TEL1 does not appear to play a major role in checkpoint function or viability, overexpression of TEL1 in a MEC1 mutant can rescue from cell death suggesting some functional redundancies between these two family members (Morrow et al, 1995). Some functional overlap also may exist between ATM and ATR/FRP1 since overexpression of the latter has recently been shown to partially complement radiosentivity and radioresistant DNA synthesis in AT ®broblasts (Cliby et al, 1998).…”

ATR is a caffeine-sensitive, DNA-activated protein kinase with a substrate specificity distinct from DNA-PK

“…In addition, the PIK family includes the TOR proteins, which are targets of the FKBP-rapamycin complex (Brown and Schreiber, 1996;Hall, 1996), and the ataxia telangiectasia gene product, ATM (Savitsky et al, 1995). A subset of the PIK family contains an additional region of homology termed the rad3 homologous region, and this subfamily includes the S. cerevisiae MEC1 and TEL1 (Greenwell et al, 1995;Morrow et al, 1995) and the Drosophila mei-41 gene product (Hari et al, 1995). Mutants in mec1, mei-41 and rad3 all display increased radiation sensitivity and are de®cient in cell cycle checkpoints which prevent mitosis in the presence of unreplicated or damaged DNA.…”

Ionizing radiation activates the ATM kinase throughout the cell cycle

“…Cells derived from A-T individuals exhibit a variety of abnormalities in culture, such as a higher requirement for serum factors, hypersensitivity to ionizing radiation and cytoskeletal defects (Morgan and Kastan 1997a;Shiloh 1995). The gene that is mutated in A-T has been designated ATM (A-T, mutated) and its product shares the PI-3 kinase signature of a growing family of proteins involved in the control of cell cycle progression, processing of DNA damage and maintenance of genomic stability (Hawley and Friend, 1996;Keith and Schreiber, 1995;Morrow et al, 1995;Savitsky et al, 1995a,b). ATM appears to be required for initiation of multiple DNA damage-dependent signal transduction cascades that activate cell-cycle checkpoints (Morgan and Kastan, 1997a;Shiloh, 1995).…”