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Results for “Recombinational DNA Repair”

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PubMed2006

Selective utilization of nonhomologous end-joining and homologous recombination DNA repair pathways during nervous system development.

The repair of DNA double-strand breaks (DSBs) occurs via nonhomologous end-joining (NHEJ) or homologous recombination (HR). These mechanistically distinct pathways are critical for maintenance of genomic integrity and organismal survival. Although inactivation of either pathway leads to embryonic lethality, here we show selective requirements for each DNA DSB repair pathway at different stages of mammalian nervous system development. DNA damage-induced apoptosis resulting from inactivation of HR (Xrcc2 deficiency) only occurred in proliferating neural precursor cells, whereas disruption of NHEJ (DNA ligase IV deficiency) mainly affected differentiating cells at later developmental stages. Therefore, these data suggest that NHEJ is dispensable for a substantial portion of early development because DSB repair during this period utilizes HR. Moreover, DNA damage-induced apoptosis required the ataxia telangiectasia mutated (Atm) kinase after disruption of NHEJ, but not HR, during neurogenesis. However, embryonic lethality arising from disruption of either repair pathway was rescued by loss of p53 and resulted in specific tumor types reflective of the particular DSB repair pathway inactivated. Thus, these data reveal distinct tissue- and cell-type requirements for each DNA DSB repair pathway during neural development and provide insights for understanding the contributions of DNA DSB responses to disease.

Animals↗
PubMed1989

The PSO4 gene is responsible for an error-prone recombinational DNA repair pathway in Saccharomyces cerevisiae.

The induction of mitotic gene conversion and crossing-over in Saccharomyces cerevisiae diploid cells homozygous for the pso4-1 mutation was examined in comparison to the corresponding wild-type strain. The pso4-1 mutant strain was found to be completely blocked in mitotic recombination induced by photoaddition of mono- and bifunctional psoralen derivatives as well as by mono- (HN1) and bifunctional (HN2) nitrogen mustards or 254 nm UV radiation in both stationary and exponential phases of growth. Concerning the lethal effect, diploids homozygous for the pso4-1 mutation are more sensitive to all agents tested in any growth phase. However, this effect is more pronounced in the G2 phase of the cell cycle. These results imply that the ploidy effect and the resistance of budding cells are under the control of the PSO4 gene. On the other hand, the pso4-1 mutant is mutationally defective for all agents used. Therefore, the pso4-1 mutant has a generalized block in both recombination and mutation ability. This indicates that the PSO4 gene is involved in an error-prone repair pathway which relies on a recombinational mechanism, strongly suggesting an analogy between the pso4-1 mutation and the RecA or LexA mutation of Escherichia coli.

Crossing Over, Genetic↗
PubMed2003

Loss of DNA recombinational repair enzymes in the initial stages of genome degeneration.

Many obligate intracellular pathogens and symbionts undergo genome degeneration during long-term association with eukaryotic hosts; however, very little is known about genome changes that occur in the initial stages of such intracellular associations. By focusing on a clade of bacteria that have recently established symbiotic associations with insect hosts, we have identified events that may contribute to the reduction and degeneration of symbiont genomes. Unlike virtually all other bacteria, the obligate symbionts of maize and rice weevils each display substantial sequence divergence between multiple copies of their rDNA genes, resulting from a reduction in the efficacy of recombinational gene conversion, coincident with the inactivation of the recombinational repair gene recF in the common ancestor of both symbionts. The maize weevil endosymbiont also lacks a functional recA, resulting in further reduction in the efficacy of gene conversion between paralogous rDNAs and in a novel IS-mediated deletion in a 23S rDNA gene. Similar events may be pervasive during the evolution of symbiosis because symbiont genomes typically lack recombinational repair genes and have reduced numbers of ribosomal operons.

Animals↗
PubMed2001

Frameshift mutations at mononucleotide repeats in RAD50 recombinational DNA repair gene in colorectal cancers with microsatellite instability.

To identify additional genes targeted for microsatellite instability (MSI), we search for human genes which contain mononucleotide repeats in their coding region, selected 7 genes (RAD50, DNA-PKcs, FLASH, Apaf-1, XPG, CtIP, and MLSN1), and analyzed frameshift mutations in them. Here we report that 60% (3 out of 5) of human colorectal cancer cell lines exhibiting a high frequency of MSI (MSI-H) and 46% (6 out of 13) of MSI-H primary colorectal tumors had mutations in the (A)9 repeat of RAD50 recombinational repair gene. In contrast, no frameshift mutations were found in any of the 5 MSI-negative colorectal cancer cell lines, 8 colorectal tumors exhibiting a low frequency of MSI (MSI-L), or 28 MSI-negative colorectal tumors. No mutations were found in the mononucleotide repeats of 6 other genes, even in MSI-H cancers. These results suggest that RAD50 frameshift mutations may play a role in the tumorigenesis of MSI-H colorectal cancers.

Colorectal Neoplasms↗
PubMed1999

A new recombinational DNA repair gene from Schizosaccharomyces pombe with homology to Escherichia coli RecA.

A new DNA repair gene from Schizosaccharomyces pombe with homology to RecA was identified and characterized. Comparative analysis showed highest similarity to Saccharomyces cerevisiae Rad55p. rhp55(+) (rad homologue pombe 55) encodes a predicted 350-amino-acid protein with an M(r) of 38,000. The rhp55Delta mutant was highly sensitive to methyl methanesulfonate (MMS), ionizing radiation (IR), and, to a lesser degree, UV. These phenotypes were enhanced at low temperatures, similar to deletions in the S. cerevisiae RAD55 and RAD57 genes. Many rhp55Delta cells were elongated with aberrant nuclei and an increased DNA content. The rhp55 mutant showed minor deficiencies in meiotic intra- and intergenic recombination. Sporulation efficiency and spore viability were significantly reduced. Double-mutant analysis showed that rhp55(+) acts in one DNA repair pathway with rhp51(+) and rhp54(+), homologs of the budding yeast RAD51 and RAD54 genes, respectively. However, rhp55(+) is in a different epistasis group for repair of UV-, MMS-, or gamma-ray-induced DNA damage than is rad22(+), a putative RAD52 homolog of fission yeast. The structural and functional similarity suggests that rhp55(+) is a homolog of the S. cerevisiae RAD55 gene and we propose that the functional diversification of RecA-like genes in budding yeast is evolutionarily conserved.

Amino Acid Sequence↗
PubMed1997

Recombinational DNA repair: the RecF and RecR proteins limit the extension of RecA filaments beyond single-strand DNA gaps.

In the presence of both the RecF and RecR proteins, RecA filament extension from a single strand gap into adjoining duplex DNA is attenuated. RecR protein alone has no effect, and RecF protein alone has a reduced activity. The RecFR complexes bind randomly, primarily to the duplex regions of the DNA, and the extension of the RecA filament is halted at the first complex encountered. A very slow lengthening of RecA filaments observed in the presence of RecFR is virtually eliminated when RecF is replaced with an RecF mutant protein that does not hydrolyze ATP. These observations are incorporated into an expanded model for the functions of RecF, RecO, and RecR proteins in the early stages of postreplication DNA repair.

Bacterial Proteins↗
PubMed2006

Significant effect of homologous recombination DNA repair gene polymorphisms on pancreatic cancer survival.

Genetic variation in DNA repair may affect the clinical response to cytotoxic therapies. We investigated the effect of six single nucleotide polymorphisms of the RecQ1, RAD54L, XRCC2, and XRCC3 genes on overall survival of 378 patients with pancreatic adenocarcinoma who were treated at University of Texas M.D. Anderson Cancer Center during February 1999 to October 2004 and were followed up to October 2005. Genotypes were determined using the MassCode method. Survival was determined from pathologic diagnosis to death. Patients who were alive at the last follow-up evaluation were censored at that time. Kaplan-Meier plot, log-rank test, and Cox regression were used to compare overall survival by genotypes. A significant effect on survival of all patients was observed for RecQ1 and RAD54L genes. The median survival time was 19.2, 14.7, and 13.2 months for the RecQ1 159 AA, AC, and CC genotypes, and 16.4, 13.3, and 10.3 months for RAD54L 157 CC, CT, and TT genotypes, respectively. A significantly reduced survival was associated with the variant alleles of XRCC2 R188H and XRCC3 A17893G in subgroup analysis. When the four genes were analyzed in combination, an increasing number of adverse alleles were associated with a significantly decreased survival. Subgroup analyses have shown that the genotype effect on survival was present among patients without metastatic disease or among patients who receive radiotherapy. These observations suggest that polymorphisms of genes involved in the repair of DNA double-strand breaks significantly affect the clinical outcome of patients with pancreatic cancer.

Adenosine Triphosphatases↗
PubMed1989

The PSO3 gene is involved in error-prone intragenic recombinational DNA repair in Saccharomyces cerevisiae.

The induction of gene conversion and mitotic crossing-over by photoaddition of psoralens, 254 nm ultraviolet radiation, and nitrogen mustards was determined in diploid cells homozygous for the pso3-1 mutation and in the corresponding wild type of Saccharomyces cerevisiae. For these different agents, the frequency of non-reciprocal events (conversion) is reduced in the pso3-1 mutant compared to the wild type. In contrast, the frequency of reciprocal events (crossing-over) is increased at a range of doses. These observations, together with the block in induced mutagenesis for both reverse and forward mutations previously reported for the pso3-1 mutant, suggest that the PSO3 gene product plays a role in mismatch repair of short patch regions. The block in gene conversion in the pso3 homozygous diploid leads, in the case of nitrogen mustards, to specific repair intermediates which are lethal to the cells.

Crossing Over, Genetic↗
PubMed1994

Effects of DNA polymerase beta gene over-expressed in transgenic Drosophila on DNA repair and recombination.

DNA polymerase beta (pol beta) cDNA of rat fused to an enhancer-promoter region plus a poly(A) signal sequence of actin 5C gene of Drosophila (abbreviated pol beta) was transferred to the Drosophila genome. Three of four constructed transgenic strains possessing transgene pol beta on different chromosomes were studied. Levels of the pol beta transcript and those of the polymerization activity of pol beta were markedly elevated in cultured cells transfected with pol beta-bearing vectors as well as in embryos of the transgenic strains. The popular idea that DNA polymerase beta participates in DNA repair was not supported by the observation that a pair of a normal and a pol beta strain, and the other pair of a mei-9 mei-41 (DNA-repair deficient double mutations) strain and a pol beta mei-9 mei-41 strain, showed no difference in survival within each pair after treatment with ultraviolet light, methylmethane sulfonate and mitomycin C. The other idea that DNA polymerase beta participates in recombination was supported by the findings that spontaneous frequency of recombination, either meiotic or mitotic, is significantly higher in a transgenic pol beta strain than in a non-transgenic strain. The enhanced recombination frequency in the pol beta strain may, however, reflect an indirect effect of over-produced pol beta proteins on chromosomal stability. Whatever the direct effect of rat pol beta is, the transgenic pol beta flies will be useful for study of the physiological role of pol beta and the mechanism of recombination.

Animals↗
PubMed1997

The Bacillus subtilis chromatin-associated protein Hbsu is involved in DNA repair and recombination.

The Bacillus subtilis hbs gene encodes an essential chromatin-associated protein termed Hbsu. Hbsu, the counterpart of the Escherichia coli HU protein, binds DNA in a non-specific way but has a clear preference for bent, kinked or altered DNA sequences. To investigate the role of Hbsu in DNA repair and DNA recombination we have constructed a series of site-directed mutants in the hbs gene and used these mutant genes to substitute the wild-type chromosomal hbs gene. The hbs47 mutation, which codes for a mutant protein in which residue Phe-47 has been replaced by Trp, does not cause any discernible phenotype. Additional substitution of residue Arg-55 by Ala (hbs4755 mutation) rendered cells deficient in DNA repair, homologous recombination and beta protein-mediated site-specific recombination. We have also tested the effect on DNA repair of the hbs4755 mutation in combination with mutations in different functions of homologous DNA recombination (recA, recF, recG, recH and addAB). The hbs4755 mutation did not modify the sensitivity of recH and addAB cells to the DNA-damaging agents methylmethane sulphonate (MMS) or 4-nitroquinoline-1-oxide (4NQO), and it only marginally affected recF and recG cells. The hbs4755 mutation blocked intermolecular recombination in recH cells and markedly reduced it (20- to 50-fold) in recF and recG cells, but had no effect on addAB cells. Taken together, these data indicate that the Hbsu protein is required for DNA repair and for homologous DNA recombination.

Amino Acid Sequence↗
PubMed2000

The histone-like protein HU binds specifically to DNA recombination and repair intermediates.

The heterodimeric HU protein associated with the Escherichia coli nucleoid shares some properties with histones and HMG proteins. HU binds DNA junctions and DNA containing a nick much more avidly than double-stranded (ds-) DNA. Cells lacking HU are extremely sensitive to gamma irradiation and we wondered how HU could play a role in maintaining the integrity of the bacterial chromosome. We show that HU binds with high affinity to DNA repair and recombination intermediates, including DNA invasions, DNA overhangs and DNA forks. The DNA structural motif that HU specifically recognizes in all these structures consists of a ds-DNA module joined to a second module containing either ds- or single-stranded (ss-) DNA. The two modules rotate freely relative to one another. Binding specificity results from the simultaneous interaction of HU with these two modules: HU arms bind the ds-DNA module whereas the HU body contacts the 'variable' module containing either ds- or ss-DNA. Both structural motifs are recognized by HU at least 1000-fold more avidly than duplex DNA.

Bacterial Proteins↗
PubMed1999

Molecular cloning and characterization of splice variants of human RAD50 gene.

In this report, splice variants of human RAD50 (hRAD50) were cloned and characterized. A Northern blot survey identified two transcripts that hybridized to a hRAD50 cDNA clone, an upper faint band (5.9kb) and lower dense band (4.6kb). cDNA clones (hRAD50-2, 4.6kb) encompassing the entire hRAD50 transcript but having a shorter 3'-untranslated region (3'UTR) than the previously reported hRAD50-1 cDNA (5.9kb; Dolganov, G.M., Maser, R.S., Novikov, A., Tosto, L., Chong, S., Bressan, D.A., Petrini, J.H.J., 1996. Human Rad50 is physically associated with human Mre11: Identification of a conserved multiprotein complex implicated in recombinational DNA repair. Mol. Cell. Biol. 16, 4832-4841.) were isolated. The presence of AU-rich sequences in the 3'UTR of hRAD50-1, which define mRNA instability and Northern results, suggest that hRAD50-2 is the major transcript of hRAD50. A third alternative splice variant that lacks the ATP-binding domain was also identified (hRAD50-3, approximately 4.5kb). Expression of hRAD50-3 transcript was detected in all tissues examined by RT-PCR (reverse transcriptase-polymerase chain reaction) and nested DNA-PCR analyses. Expression of hRAD50 partially rescued the MMS (methyl methanesulfonate)-sensitive phenotype in rad50 mutant yeast, whereas hRAD50-3 did not show complementation. These data suggest that the hRAD50-3 does not repair DNA double-strand breaks most likely due to its inability to bind ATP, and to bind damaged DNA. The existence of these alternative splice forms is potentially important in regulation of the biological activity of the DNA recombinational repair gene, hRAD50.

3' Untranslated Regions↗