Ataxia-telangiectasia (AT) is one of several rare inherited disorder in humans which are characterized by defects in cellular responses to DNA damage (in particular from ionizing radiation) and an increased risk. A gene, ATM, which is mutated in patients with AT, has been cloned. Characterization of the normal function of the product of the ATM gene and the effects of mutations observed in AT patients, should help to elucidate the pathways and molecules that mediate responses to radiation in normal human cells. The proposed study builds on our 9 years of experience with linkage mapping and positional cloning in AT and our collection of cell lines and DNA from AT patients and their families to address 2 aims: (1) to fully characterize sequence variation in the ATM gene in a panel of AT cell lines and (2) to determine the effects of site directed mutations on the function of ATM and its role in cellular radiation responses. Sequence comparisons reveal significant homologies between ATM in humans and the products of genes in yeast that are involved in sensing and responding to DNA damage. This suggests that an exploration of the function of not just ATM but also other human homologies of yeast genes involved in damage response pathways may be helpful in elucidating the pathways and molecular interactions involved in radiation responses in humans.
A third aim exploits this parallel, focusing on possible interactions and/or functional overlap between ATM and the human homologue of S. pombe Rad3. The vast majority of families displaying the classic AT phenotype link to the 11q23 region where the ATM gene is located. However, a clinical variant of AT, Nijmegen Breakage Syndrome (NBS), which shares the radiation sensitivity, chromosomal instability and high cancer incidence phenotypes of AT, does not result from mutations in ATM.
A fourth aim proposes to continue our linkage studies in NBS to identify the gene involved. The overlap in phenotypes between AT and NBS suggests that NBS may result from defects in a second molecule in the same or a related pathway as ATM. Thus, identification of the NBS gene may shed further light on the function of ATM as well as providing additional insight into the pathways and components of cellular responses to radiation, in general.
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