ATM-related genes: What do they tell us about functions of the human gene?

Every time a cell divides, it must duplicate and segregate its chromosomes. Eukaryotic cells carry out these processes with remarkable order and fidelity. For example, in the yeast Saccharomyces cerevisiae, chromosome loss occurs at rates of only-10-5 per cell division. This precision is achieved at four levels. First, chromosomes bear replication origins, centromeres, and telomeres, cis-acting structures essential for their stable maintenance. Second, there are many transacting factors, such as replication enzymes and spindle components, integral to the processes of replication and segregation. Third, there are cell cycle checkpoints, regulatory mechanisms that delay cell cycle progression when defects are detected in essential genetic structures, allowing repair prior to cell division. Finally, there are the repair activities themselves, activities that correct spontaneous or induced damage to the ge-nome. Although checkpoint and repair genes contribute to chromosome stability, genes whose sole function is to detect or repair DNA damage are not expected to be essential in the absence of DNA damage. Some genes act at multiple levels in ensuring genome integrity. For example , in Saccharomyces, DNA polymerase ~ serves not only as an essential replication enzyme but also as an S phase checkpoint gene and possibly as a DNA repair activity (Navas et al., 1995, and references therein). Ataxia telangiectasia (AT) is a human autosomal hereditary disease characterized by a wide spectrum of defects, including cerebellar degeneration, progressive mental retardation , uneven gait (ataxia), dilation of blood vessels (telangiectasia), immune deficiencies, premature aging, and an-100-fold increase in cancer susceptibility (reviewed by Friedberg et al., 1995). Identification of the gene mutated in individuals suffering from AT revealed that most or all cases of this heterogeneous disease are caused by mutation of a single gene called ATM (Savitsky et al., 1995). Since some affected individuals carry ATM alleles that eliminate essentially the entire open reading frame (ORF), ATM is not an essential gene (Savitsky et al., 1995). Although the disease is recessive and relatively rare, heterozygotes, who make up-1% of the population, also have an increased cancer risk. For example, it is estimated that heterozygosity at the ATM locus accounts for >/9% of breast cancers in the United States (Swift et al., 1991; reviewed by Friedberg et al., 1995). Thus, understanding the mechanism of action of ATM is of considerable practical significance. At the cellular level, AT is characterized by chromosome abnormalities, including elevated numbers of spontaneous and radiation-induced chromosome breaks and telo-mere-telomere …