The D. melanogaster mei-41 gene is required for DNA repair, mitotic chromosome stability, and normal levels of meiotic recombination in oocytes. Here we show that the predicted mei-41 protein is similar in sequence to the ATM (ataxia telangiectasia) protein from humans and to the yeast rad3 and Mec1p proteins. There is also extensive functional overlap between mei-41 and ATM. Like ATM-deficient cells, mei-41 cells are exquisitely sensitive to ionizing radiation and display high levels of mitotic chromosome instability. We also demonstrate that mei-41 cells, like ATM-deficient cells, fail to show an irradiation-induced delay in the entry into mitosis that is characteristic of normal cells. Thus, the mei-41 gene of Drosophila may be considered to be a functional homolog of the human ATM gene.
Mutations in the Drosophila mus308 gene confer specific hypersensitivity to DNA-cross-linking agents as a consequence of defects in DNA repair. The mus308 gene is shown here to encode a 229-kDa protein in which the amino-terminal domain contains the seven conserved motifs characteristic of DNA and RNA helicases and the carboxy-terminal domain shares over 55% sequence similarity with the polymerase domains of prokaryotic DNA polymerase I-like enzymes. This is the first reported member of this family of DNA polymerases in a eukaryotic organism, as well as the first example of a single polypeptide with homology to both DNA polymerase and helicase motifs. Identification of a closely related gene in the genome of Caenorhabditis elegans suggests that this novel polypeptide may play an evolutionarily conserved role in the repair of DNA damage in eukaryotic organisms.
The mus209B1 mutant of Drosophila melanogaster exhibits a complex pleiotropy of temperature‐sensitive (ts) lethality, hypersensitivity to DNA‐damaging agents such as ionizing radiation and methyl methanesulfonate, suppression of position‐effect variegation (PEV), and female sterility. Our discovery that mus209 encodes proliferating cell nuclear antigen (PCNA), which is an indispensable component of the DNA replication apparatus, suggests that alterations to chromosome replication may underlie that pleiotropy. Nine lethal mutations, three of them ts, genetically define the Pcna locus. Temperature shift studies reveal that the vital function of PCNA is required throughout virtually all stages of fly development, and that maternally encoded PCNA is essential for embryogenesis. All three ts mutants strongly suppress PEV, which suggests a role for PCNA in chromatin assembly or modification.
Recombination-defective meiotic mutants and mutagen-sensitive mutants of D. melanogaster have been examined for their effects on meiotic chromosome behavior, sensitivity to killing by mutagens, somatic chromosome integrity, and DNA repair processes. Several loci have been identified that specify functions that are necessary for both meiotic recombination and DNA repair processes, whereas mutants at other loci appear to be defective in only one pathway of DNA processing. Mutational analyses of prokaryotic systems have established that DNA replication, repair, and recombination are, in part, under common genic control (1-3). Although there are strong theoretical grounds for extending this conclusion to eukaryotes in general (4-7), direct experimental evidence for an interrelation of the various pathways of DNA metabolism in organisms that undergo meiosis comes primarily from studies of fungi (8, 9). Recombination-defective and repair-defective mutants have been reported in other eukaryotes (9, 10), although in most instances it is not known whether these mutants affect more than one pathway of DNA processing.In Drosophila melanogaster two classes of mutants with potential effects on DNA metabolism have been reported. First, substantial numbers of meiotic mutants are available, which were recognized because they produce genetically detectable abnormal meiotic chromosome behavior (for reviews see refs. 9, 11-14). Mutants at 12 loci are defective in processes essential for normal exchange (frequency and/or distribution along the chromosome) and are thus recombination-defective mutants. Watson (15,16) presented evidence that one of these recombination-defective mutants, c(3)G 17, is more susceptible than wild type to the induction of mutants and rearrangements during meiosis, and on this basis has suggested that the product of c(3)G + functions in both repair and recombination. Second, mutagen-sensitive mutants have been isolated on the basis of hypersensitivity to killing by methylmethanesulfonate (MMS) (17, 18,t). The characterization of meiotic mutants and mutagen-sensitive mutants (18, 19, ¶) by three separate groups using a variety of approaches has led to the realization that overlapping sets of mutants are being examined. In this preliminary communication we coordinate the results of the three groups and outline the conclusions concerning the relation between the genic controls of DNA repair processes and meiotic recombination in Drosophila. We focus here primarily on studies of several selected X-linked mutagen-sensitive and meiotic mutants. The detailed data on the arrays of mutants from which our conclusions have been derived will be published elsewhere.Known X-linked recombination-defective and/or mutagen-sensitive loci Recombination-defective mutants are known at 5 X chromosomal loci; mei-9, nmwi-218, me i-41, mei-352, and mei-251 (20, 21). In addition to decreasing the frequency and/or altering the distribution of exchanges along the chromosomes during female meiosis, these mutants all produce el...
SUMMARY Overview Mutant isolation and characterization Mutant sources Mutagen-sensitive mutants (mus) Meiotic mutants (mei) Mutations producing gene and chromosome instability Genetic and cytological analyses Mutant influences on meiosis Mutant influences on mutation Identification of defects in DNA repair Photorepair Excision repair Postreplication repair Additional repair processes Molecular cloning of DNA repair genes Cloning strategy Mutation induction by transposon tagging Progress report Enzymology related to DNA repair
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