Genetic analysis of X-linked mutagen-sensitive mutants of Drosophila melanogaster

Mason, James; Green, M.M.; Shaw, Katharina S.; Boyd, James B.

doi:10.1016/0027-5107(81)90120-2

Cited by 37 publications

(16 citation statements)

References 19 publications

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“…Dmp53 null mutants have degenerative ovarioles and decreased fertility compared with their parental strain (Lee et al 2003). Interestingly, decreased fertility is also observed in mei-41 and Dmchk2 null Drosophila (Mason et al 1981;Banga et al 1995;Brodsky et al 2000b;Xu et al 2001). The products of these genes are homologous to mammalian DNA damage-induced kinases, ATM and Chk2, respectively, which activate p53 protein on DNA damage (Canman et al 1998;Hirao et al 2000;Shieh et al 2000).…”

Section: The Primordial Functions Of the P53 Family Genes In Invertebmentioning

confidence: 99%

The Role of p53 Gene Family in Reproduction

2009

Cold Spring Harbor Perspectives in Biology

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The p53 family of genes ( p53, p63, and p73) is conserved over evolutionary time scales. Although the functions of p53 gene and its protein as a tumor suppressor have been firmly established, the earliest functions for the p53 ancestral genes in worms and flies are to ensure germ-line genomic integrity and the fidelity of the developmental process. In vertebrates, the p53 family of genes retains those functions in germ-line genomic integrity but have added important functions in regulation of reproduction. Loss of the p53, p63, or p73 genes in female mice leads to a significant decrease of fertility. The p53 gene product regulates maternal reproduction at the implantation stage of the embryo. p63 and p73 play important roles in monitoring the genomic quality of oocytes. The p53 pathway appears to play a similar role in human fertility. In humans, certain alleles containing a functional single-nucleotide polymorphism (SNP) in the p53 pathway are under positive evolutionary selection. Selected alleles of these SNPs in the p53 pathway are associated with decreased fertility. This important function of the p53 pathway in reproduction provides a plausible explanation for the evolution of p53 as a tumor suppressor gene and the positive selection of some alleles in the p53 gene and its pathway. These observations provide a good possible example of antagonistic pleiotrophy for fertility, tumor suppression, and longevity.

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Section: The Primordial Functions Of the P53 Family Genes In Invertebmentioning

confidence: 99%

The Role of p53 Gene Family in Reproduction

2009

Cold Spring Harbor Perspectives in Biology

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“…As a positive control, we conducted simultaneous assays of sensitivity on mei-41 29D mutants. This gene encodes the Drosophila ortholog of ATR, which is required for the DNA-damage-dependent cell cycle checkpoint (Hari et al 1995); mei-41 mutants are hypersensitive to a wide range of DNA-damaging agents (Boyd et al 1976;Nguyen et al 1979;Mason et al 1981;Banga et al 1986). We did not detect hypersensitivity of mus81…”

Section: Mus81mentioning

confidence: 99%

Synthetic Lethality of Drosophila in the Absence of the MUS81 Endonuclease and the DmBlm Helicase Is Associated With Elevated Apoptosis

et al. 2007

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Mus81-Mms4 (Mus81-Eme1 in some species) is a heterodimeric DNA structure-specific endonuclease that has been implicated in meiotic recombination and processing of damaged replication forks in fungi. We generated and characterized mutations in Drosophila melanogaster mus81 and mms4. Unlike the case in fungi, we did not find any role for MUS81-MMS4 in meiotic crossing over. A possible role for this endonuclease in repairing double-strand breaks that arise during DNA replication is suggested by the finding that mus81 and mms4 mutants are hypersensitive to camptothecin; however, these mutants are not hypersensitive to other agents that generate lesions that slow or block DNA replication. In fungi, mus81, mms4, and eme1 mutations are synthetically lethal with mutations in genes encoding RecQ helicase homologs. Similarly, we found that mutations in Drosophila mus81 and mms4 are synthetically lethal with null mutations in mus309, which encodes the ortholog of the Bloom Syndrome helicase. Synthetic lethality is associated with high levels of apoptosis in proliferating tissues. Lethality and elevated apoptosis were partially suppressed by a mutation in spn-A, which encodes the ortholog of the strand invasion protein Rad51. These findings provide insights into the causes of synthetic lethality.

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“…Identification of snm1: As noted above, our screen identified only seven lines that were uniquely hypersensitive to HN2. Of the seven new mutants, three were which we recovered MMS-sensitive mutants was ‫-5ف‬fold higher than the frequency (0.3%, 31/11,334) of MMSdetermined to be alleles of mus308, the only previously characterized Drosophila gene whose mutant phenosensitive mutants previously obtained (Boyd et al 1981) from third chromosomes mutagenized at an ‫-01ف‬fold type included hypersensitivity only to agents capable of creating DNA interstrand crosslinks (Boyd et al 1990), lower dose (3 mm) of EMS.…”

Section: Methodsmentioning

confidence: 99%

“…Twenty-two DNA repair genes on the second and TM6B. Our screen compared the viability of mutagenized third chromosomes were likewise identified in screens homozygotes to that of their mutagenized balancer heterozyfor new mus mutants (Boyd et al 1981;Snyder and gote siblings. Mutant lines in which the frequency of homozy- Smith 1982;Henderson et al 1987).…”

Section: Methodsmentioning

confidence: 99%

“…The netic screens for mutagen-sensitive (mus) mutants have mutagenized autosomes were isolated over second-or thirdchromosome balancers, and the stocks were provided and identified 8 DNA repair genes on the X chromosome maintained in this state. The collection arrived in batches of (Boyd et al 1976(Boyd et al , 1981 Smith 1976; Nguyen et al 1978; 600 lines each week over a total of 7 months. All mutant Yamamoto et al 1990;Leonhardt and Boyd 1993), in lines were maintained at room temperature on a standard addition to two mutagen-sensitive loci (mei-9 and mei-41) cornmeal-dextrose medium.…”

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A Large-Scale Screen for Mutagen-Sensitive Loci in Drosophila

et al. 2004

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In a screen for new DNA repair mutants, we tested 6275 Drosophila strains bearing homozygous mutagenized autosomes (obtained from C. Zuker) for hypersensitivity to methyl methanesulfonate (MMS) and nitrogen mustard (HN2). Testing of 2585 second-chromosome lines resulted in the recovery of 18 mutants, 8 of which were alleles of known genes. The remaining 10 second-chromosome mutants were solely sensitive to MMS and define 8 new mutagen-sensitive genes (mus212-mus219). Testing of 3690 third chromosomes led to the identification of 60 third-chromosome mutants, 44 of which were alleles of known genes. The remaining 16 mutants define 14 new mutagen-sensitive genes (mus314-mus327). We have initiated efforts to identify these genes at the molecular level and report here the first two identified. The HN2-sensitive mus322 mutant defines the Drosophila ortholog of the yeast snm1 gene, and the MMS-and HN2-sensitive mus301 mutant defines the Drosophila ortholog of the human HEL308 gene. We have also identified a second-chromosome mutant, mus215 ZIII-2059 , that uniformly reduces the frequency of meiotic recombination to Ͻ3% of that observed in wild type and thus defines a function required for both DNA repair and meiotic recombination. At least one allele of each new gene identified in this study is available at the Bloomington Stock Center.T HE ability of cells to reproduce their genome accu-reactive species generated through normal cellular oxidative metabolism. rately requires both continuous monitoring of theThe repair of such disparate types of damage requires integrity of the DNA complement and efficient repair the action of a variety of qualitatively different DNA of damage to the DNA. Coordination of these processes repair systems. To date, there is biochemical and genetic is required for proper completion of DNA replication evidence from bacteria, yeast, and other higher eukaryoand cell division, and it is crucial that cells be able to tic systems for Ͼ130 distinct proteins involved in recogrecognize damaged or incompletely replicated DNA to nition and repair of DNA damage (Wood et al. 2001). halt the cell cycle while damage is repaired and, most Some of these proteins function quite specifically in critically, to accurately repair that damage. In higher repairing or removing damaged DNA (e.g., photolyase), eukaryotes, impediments to repair can lead to high frewhile others (e.g., DNA ligases) play more general roles quencies of mutation, cancer, and in some cases, cell in cellular metabolism in addition to their specific funcor organismal death. DNA damage involves a variety tions in repair. There are five major categories of DNA of molecular lesions, including double-strand breaks repair, as reviewed in detail (Friedberg et al. 1995). (DSBs) of the DNA duplex, nicks in a single strand, These include damage reversal, in which the chemical creation of abasic sites, and a plethora of covalent chemalteration to the DNA molecule is reversed to restore ical modifications. These modifications include covathe ori...

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Genetic analysis of X-linked mutagen-sensitive mutants of Drosophila melanogaster

Cited by 37 publications

References 19 publications

The Role of p53 Gene Family in Reproduction

The Role of p53 Gene Family in Reproduction

Synthetic Lethality of Drosophila in the Absence of the MUS81 Endonuclease and the DmBlm Helicase Is Associated With Elevated Apoptosis

A Large-Scale Screen for Mutagen-Sensitive Loci in Drosophila

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