Chemistry: molecular biology and microbiology – Measuring or testing process involving enzymes or... – Involving nucleic acid
Patent
1996-11-05
2000-03-14
Ketter, James
Chemistry: molecular biology and microbiology
Measuring or testing process involving enzymes or...
Involving nucleic acid
C12Q 168
Patent
active
060371250
ABSTRACT:
When a mutation, designated rad51.sup.M1, was generated in the mouse MmRAD51 gene, mutant embryos died shortly after implantation. rad51.sup.M1 cells exhibited hypersensitivity to ionizing radiation, reduced proliferation, programmed cell death and chromosome loss. The disruption of MmRad51 rotein-protein interactions stopped cell proliferation and/or reduced cell viability. Several proteins that interact with MmRad51 have been identified including, for example Brca2 and M96. Additionally, Rad51 self-associates via the N-terminal region. When a single residue was changed from a conserved lysine to an alanine, the alteration proved toxic to cells. Moreover, a rad51 allele that lacked the RecA homology region was also deleterious to cells. In view of the above, it is clear that inhibiting MmRad51 function or the function of any molecule that associates with MmRad51, or any molecule in the Rad51 or Rad52 pathways, hinders cell proliferation and/or viability. Accordingly, molecules capable of blocking these critical DNA repair pathways may be effective as therapeutics for inhibiting cell proliferation.
REFERENCES:
Shen et al., J. Biol. Chem., vol. 271, 1996, pp. 148-152.
Aboussekhra et al., 1992, "Semidominant Suppressors of Srs2 Helicase Mutations of Saccharomyces cerevisiae Map in the RAD51 Gene, Whose Sequence Predicts a Protein with Similarities to Procaryotic RecA Proteins," Mol. Cell. Biol. 12:3224-3234.
Ashley et al., 1995, "Dynamic changes in Rad51 distribution on chromatin during meiosis in male and female vertebrates," Chromosoma 104:19-28.
Baker et al., 1990, "Suppression of Human Colorectal Carcinoma Cell Growth by Wild-Type p53," Science 249:912-915.
Basile et al., 1992, "Nucleotide Sequence and Transcriptional Regulation of the Yeast Recombinational Repair Gene RAD51," Mol. Cell. Biol. 12:3235-3246.
Bendixen et al., 1994, "Identification of a Mouse Homologue of the Saccharomyces cerevisiae Recombination and Repair Gene, RAD52," Genomics 23:300-303.
Bennett et al., 1993, "Lethality induced by a single site-specific double-strand break in a dispensable yeast plasmid," Proc. Natl. Acad. Sci. U.S.A. 90:5613-5617.
Benson et al., 1994, "Purification and characterization of the human Rad51 protein, an analogue of E. coli RecA," EMBO Journal 13:5764-5771.
Bezzubova et al., 1993, "A chicken RAD51 homologue is expressed at high levels in lymphoid and reproductive organs," Nucleic Acids Res. 21:1577-1580.
Bishop, 1994, "RecA Homologs Dmc1 and RAD51 Interact to Form Multiple Nuclear Complexes Prior to Meiotic Chromosome Synapsis," Cell 79:1081-1092.
Bradley et al., 1992, "Modifying the Mouse: Design and Desire," Bio/Technology 10:534-539.
Carr and Hoekstra, 1995, "The cellular responses to DNA damage," Trends in Cell Biology 5:32-40.
Cleaver, 1994, "It Was Very Good Year for DNA Repair," Cell 76:1-4.
Derossi et al., 1994, "The Third Helix of the Antennapedia Homeodomain Translocates through Biological Membranes," J. Biol. Chem. 269:10444-10450.
Donehower et al., 1992, "Mice deficient for p53 are developmentally normal but susceptible to spontaneous tumours," Nature 356:215-221.
Donovan et al., 1994, "Homotypic and heterotypic protein associations control Rad51 function in double-strand break repair," Genes and Develop. 8:2552-2562.
Haaf et al., 1995, "Nuclear foci of mammalian Rad51 recombination protein in somatic cells after DNA damage and its localization in symanptonemal complexes," Proc. Natl. Sci. U.S.A. 92:2298-2302.
Habu et al., 1996, "The mouse and human homologs of DMC1, the yeast meiosis-specific homologous recombination gene, have a common unique form of exon-skipped transcript in meiosis," Nucleic Acids Res. 24:470-477.
Harvey et al., 1993, "In vitro growth characteristics of embryo fibroblasts isolated from p53-deficient mice," Oncogene 8:2457-2467.
Hays et al., 1995, "Complex formation in yeast double-strand break repair: Participation of Rad51, Rad52, Rad55 and Rad57 proteins," Proc. Natl. Acad. Sci. U.S.A. 92:6925-6929.
Horii et al., 1992, "Inhibitory Effects of N- and C-terminal Truncated Escherichia coli recA Gene Products on Functions of the Wild-type recA Gene," J. Mol. Biol. 223:105-114.
Inouye et al., 1994, "Isolation of cDNA Encoding a Metal Response Element Binding Protein Using a Novel Expression Cloning Procedure: The One Hybrid System," DNA Cell. Biol. 13(7):731-742.
Jang et al., 1994, "Cloning and sequencce analysis of rhp51.sup.+, a Schizosaccharomyces pombe homolog of the Saccharomyces cerevisiae RAD51 gene," Gene 142:207-211.
Jeggo, 1990, "Studies on mammalian mutants defective in rejoining double-strand breaks in DNA," Mutation Research 239:1-16.
Johnson and Symington, 1995, "Functional Differences and Interactions among the Putative RecA Homologs Rad51, Rad55, and Rad57," Mol. Cell. Biol. 15:4843-4850.
Kastan et al., 1991, "Participation of p53 Protein in the Cellular Response to DNA Damage," Cancer Research 51:6304-6311.
Kirchgessner et al., 1995, "DNA-Dependent Kinase (p350) as a Candidate Gene for the Murine SCID Defect," Science 267:1178-1183.
Ko and Prives, 1996, "p53: puzzle and paradigm," Genes and Develop. 10:1054-1072.
Krasin and Hutchinson, 1977, "Repair of DNA Double-strand Breaks in Escherichia coli, which Requires recA Function and the Presence of a Duplicate Genome," J. Mol. Biol. 116:81-98.
Kuerbitz et al., 1992, "Wild-type p53 is a cell cycle checkpoint determinant following irradiation," Proc. Natl. Acad. Sci. U.S.A. 89:7491-7495.
Liang et al., 1996, "Chromosomal double-strand break repair in Ku80-deficient cells," Proc. Natl. Acad. Sci. U.S.A. 93:8929-8933.
Lim and Hasty, 1996, "A mutation in mouse rad51 results in an early embryonic lethal that is suppressed by a mutation in p53," Mol. Cell. Biol. 16(12):7133-7143.
Lowe et al., 1994, "p53 Status and the Efficacy of Cancer Therapy in Vivo," Science 266:807-810.
Lu and Lane, 1993, "Differential Induction of Transcriptionally Acive p53 Following UV or lonizing Radiation: Defects in Chromosome Instability Syndromes?" Cell 75:765-778.
Malkova et al., 1996, "Double-strand break repair in the absence of RAD51 i yeast: A possible role for break-induced DNA replication," Proc. Natl. Acad. Sci. U.S.A. 93:7131-7136.
Milne and Weaver, 1993, "Dominant negative alleles of RAD52 reveal a DNA repair/recombination complex including Rad51 and Rad52," Genes and Develop. 7:1755-1765.
Morita et al., 1993, "A mouse homolog of the Escherichia coli recA and Saccharomyces cerevisiae RAD51 genes," Proc. Natl. Acad. Sci. U.S.A. 90:6577-6580.
Mortimer, 1958, "Radiobiological and Genetic Studies on a Polyploid Series (Haploid to Hexaploid) of Saccharomyces cerevisiae," Radiat. Res. 9:312-326.
Muris et al., 1993, "Cloning the RAD51 homologue of Schizosaccharomyces pombe," Nucleic Acids Res. 21:4586-4591.
Norioka et al., 1995, "Two recA Genes in Myxococcus xanthus," J. Bacteriol. 177:4179-4182.
Nussenzweig et al., 1996, "Requirement for Ku80 in growth and immunoglobulin V(D)J recombination," Nature 382:551-555.
Park et al., 1996, "Physical Interaction between human Rad52 and RPA Is Required for Homologous Recombination in Mammalian Cells," J. Biol. Chem. 1996:18996-19000.
Resnick et al., 1989, "Lack of DNA homology in a pair of divergent chromosomes greatly sensitizes them to loss by DNA damage," Proc. Natl. Acad. Sci. U.S.A. 86:2276-2280.
Rockmill et al., 1995, "Roles for two RecA homologs in promoting meiotic chromosome synapsis," Genes and Develop. 9:2684-2695.
Schiestl et al., 1989, "Cloning and Sequence Analysis of the Saccharomyces cerevisiae RAD9 Gene and Further Evidence that Its Product is Required for Cell Cycle Arrest Induced by DNA Damage," Mol. Cell. Biol. 9:1882-1896.
Schlissel et al., 1993, "Double-strand signal sequence breaks in V(D)J recombination are blunt, 5'-phosphorylated, RAG-dependent, and cell cycle regulated," Genes and Develop. 7:2520-2532.
Shen et al., 1995, "The Human and Mouse Homologs of the Yeast RAD52 Gene: cDNA Cloning, Sequence Analysis, Assignment to Human Chromosome 12p12.2-p13, and mRNA Expression in Mouse Tissues," Genomics 25:199-206.
Shen et al., 1996, "Specific Int
Ketter James
Lexicon Genetics Incorporated
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