Molecular genetic characterization ofDrosophilaATM conserved functional domains

Abstract

ATM-related kinases promote repair of DNA double-strand breaks and maintenance of chromosome telomeres, functions that are essential for chromosome structural integrity in all eukaryotic organisms. In humans, loss of ATM function is associated with ataxia telangiectasia, a neurodegenerative disease characterized by extreme sensitivity to DNA damage. Drosophila melanogaster has recently emerged as a useful animal model for analyzing the molecular functions of specific domains of this large, multifunctional kinase. The gene encoding Drosophila ATM kinase (dATM) was originally designated tefu because of the telomere fusion defects observed in atm mutants. In this report, molecular characterization of eight atm (tefu) alleles identified nonsense mutations predicted to truncate conserved C-terminal domains of the dATM protein, as well as two interesting missense mutations. One of these missense mutations localized within a putative HEAT repeat in the poorly characterized N-terminal domain of dATM (atm4), whereas another associated with a temperature-sensitive allele (atm8) changed the last amino acid of the conserved FATC domain. Leveraging this molecular information with the powerful genetic tools available in Drosophila should facilitate future analysis of conserved ATM-mediated molecular mechanisms that are important for telomere maintenance, DNA repair, and neurodegeneration.