Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Werner syndrome (WRN) is an uncommon autosomal recessive disease whose phenotype includes features of premature aging, genetic instability, and an elevated risk of cancer. We used three different experimental strategies to show that WRN cellular phenotypes of limited cell division potential, DNA damage hypersensitivity, and defective homologous recombination (HR) are interrelated. WRN cell survival and the generation of viable mitotic recombinant progeny could be rescued by expressing wild-type WRN protein or by expressing the bacterial resolvase protein RusA. The dependence of WRN cellular phenotypes on RAD51-dependent HR pathways was demonstrated by using a dominant-negative RAD51 protein to suppress mitotic recombination in WRN and control cells: the suppression of RAD51-dependent recombination led to significantly improved survival of WRN cells following DNA damage. These results define a physiological role for the WRN RecQ helicase protein in RAD51-dependent HR and identify a mechanistic link between defective recombination resolution and limited cell division potential, DNA damage hypersensitivity, and genetic instability in human somatic cells.
Mol Cell Biol 2002 Oct
PMID:Homologous recombination resolution defect in werner syndrome. 1224 78

African trypanosomes are unicellular parasites that use DNA recombination to evade the mammalian immune response. They do this in a process called antigenic variation, in which the parasites periodically switch the expression of VSG genes that encode distinct Variant Surface Glycoprotein coats. Recombination is used to move new VSG genes into specialised bloodstream VSG transcription sites. Genetic and molecular evidence has suggested that antigenic variation uses homologous recombination, but the detailed reaction pathways are not understood. In this study, we examine the recombination pathways used by trypanosomes to integrate transformed DNA into their genome, and show that they possess at least two pathways of homologous recombination. The primary mechanism is dependent upon RAD51, but a subsidiary pathway exists that is RAD51-independent. Both pathways contribute to antigenic variation. We show that the RAD51-independent pathway is capable of recombining DNA substrates with very short lengths of sequence homology and in some cases aberrant recombination reactions can be detected using such microhomologies.
Mol Microbiol 2002 Sep
PMID:Two pathways of homologous recombination in Trypanosoma brucei. 1235 34

Fanconi anemia (FA) is a cancer-predisposition syndrome characterized by hypersensitivity to interstrand-cross-link (ICL) inducers. FA hypersensitivity to ICL has been correlated with alterations in homologous recombination, non-homologous end-joining, telomere maintenance, DNA-damage assessment and checkpoint regulation, processes in which the components of the RAD50/MRE11/NBS1 (RMN) complex are involved. To better characterize the mechanisms by which ICL are processed in human cells and to gain insight into their toxicity in FA, we examined (i). the RMN complex assembling in response to the ICL inducers mitomycin C (MMC) and photoactivated 8-methoxypsoralen and (ii). the proficiency of FA cells to perform RMN activation in response to ICL inducers. We show here that ICL activates the assembly of the RMN proteins into subnuclear foci, and that their formation proceeds independently of ICL incision, a step mainly dependent on XP-F/ERCC1 heterodimer activity. Interestingly, FA cells were unable to form RMN foci in response to either ICL inducer. Analysis by pulsed-field gel electrophoresis and single-cell gel electrophoresis of MMC-treated cells showed that FA cells from complementation group C (FA-C cells, defective in the FANCC gene) form double-strand breaks and unhook MMC-induced ICL similarly to FANCC wild-type cells. These observations imply that the absence of RMN assembly in FA-C cells is not simply due to the absence of DNA ends produced as intermediates of ICL processing, and indicates a direct role for FANCC in RMN focus assembly in response to ICL inducers. Moreover, we show that the formation of foci, including BRCA1 and/or RAD51 proteins, is significantly delayed in FA cells. These alterations in the assembly of DNA-repair proteins in FA provide an interpretation for the DNA-damage processing anomalies observed in FA cells and for the genetic instability and the cancer predisposition of the syndrome.
Hum Mol Genet 2002 Oct 01
PMID:DNA cross-link-dependent RAD50/MRE11/NBS1 subnuclear assembly requires the Fanconi anemia C protein. 1235 79

The process of homologous recombination is a major DNA repair pathway that operates on DNA double-strand breaks, and possibly other kinds of DNA lesions, to promote error-free repair. Central to the process of homologous recombination are the RAD52 group genes (RAD50, RAD51, RAD52, RAD54, RDH54/TID1, RAD55, RAD57, RAD59, MRE11, and XRS2), most of which were identified by their requirement for the repair of ionizing-radiation-induced DNA damage in Saccharomyces cerevisiae. The Rad52 group proteins are highly conserved among eukaryotes, and Rad51, Mre11, and Rad50 are also conserved in prokaryotes and archaea. Recent studies showing defects in homologous recombination and double-strand break repair in several human cancer-prone syndromes have emphasized the importance of this repair pathway in maintaining genome integrity. Although sensitivity to ionizing radiation is a universal feature of rad52 group mutants, the mutants show considerable heterogeneity in different assays for recombinational repair of double-strand breaks and spontaneous mitotic recombination. Herein, I provide an overview of recent biochemical and structural analyses of the Rad52 group proteins and discuss how this information can be incorporated into genetic studies of recombination.
Microbiol Mol Biol Rev 2002 Dec
PMID:Role of RAD52 epistasis group genes in homologous recombination and double-strand break repair. 1245 86

The proteins encoded by the breast-cancer-susceptibility genes, BRCA1 and BRCA2, have recently been implicated in DNA-repair processes, thereby improving our understanding of how the loss of these genes contributes to cancer initiation and progression. It appears that the role of BRCA1 in DNA repair, which could involve the integration of several pathways, is broader than that of BRCA2. BRCA1 functions in the signalling of DNA damage and its repair by homologous recombination, nucleotide-excision repair and possibly non-homologous end-joining. BRCA2 has a more specific role in DNA repair, regulating the activity of RAD51, which is required for homologous recombination. An improved understanding of the interactions of BRCA1 and BRCA2 with other proteins in large macromolecular complexes is helping to reveal their exact role in DNA repair.
Trends Mol Med 2002 Dec
PMID:The relationship between the roles of BRCA genes in DNA repair and cancer predisposition. 1247 Sep 90

Inherited mutations of the BRCA1 and BRCA2 genes, whose protein products are necessary for the homology-directed DNA repair pathway, confer a dominant susceptibility to cancer. We have investigated whether mutations of genes encoding other components of the same DNA repair pathway can also affect cancer susceptibility. We have identified three novel non-synonymous substitutions in one such gene, encoding the RAD51-related protein XRCC3. One of these variants, D213N, occurs in a highly conserved ATP-binding domain and completely abrogates the ability of the transfected gene to correct the phenotype of XRCC3 deficient cells. The D213N variant was found in the heterozygous state in DNA from 3/1577 healthy individuals. However, we did not detect this variant at all amongst 187 breast cancer families and 1300 unrelated patients with common cancers. Thus we have no evidence that D213N increases the risk of cancer. We propose that not all components of the homologous recombination repair complex can act as cancer susceptibility genes.
Hum Mol Genet 2003 Apr 15
PMID:A naturally occurring mutation in an ATP-binding domain of the recombination repair gene XRCC3 ablates its function without causing cancer susceptibility. 1266 15

The RAD51 protein, a eukaryotic homologue of the Escherichia coli RecA protein, plays an important role in the repair of DNA double-strand breaks (DSBs) by homologous recombination (HR) in mammalian cells. Recent findings suggest that HR may be important in repair following replication arrest in mammalian cells. Here, we have investigated the role of RAD51 in the repair of different types of damage induced during DNA replication with etoposide, hydroxyurea or thymidine. We show that etoposide induces DSBs at newly replicated DNA more frequently than gamma-rays, and that these DSBs are different from those induced by hydroxyurea. No DSB was found following treatment with thymidine. Although these compounds appear to induce different DNA lesions during DNA replication, we show that a cell line overexpressing RAD51 is resistant to all of them, indicating that RAD51 is involved in repair of a wide range of DNA lesions during DNA replication. We observe fewer etoposide-induced DSBs in RAD51-overexpressing cells and that HR repair of etoposide-induced DSBs is faster. Finally, we show that induced long-tract HR in the hprt gene is suppressed in RAD51-overexpressing cells, although global HR appears not to be suppressed. This suggests that overexpression of RAD51 prevents long-tract HR occurring during DNA replication. We discuss our results in light of recent models suggested for HR at stalled replication forks.
J Mol Biol 2003 May 02
PMID:RAD51 is involved in repair of damage associated with DNA replication in mammalian cells. 1270 14

Fanconi anaemia (FA) is an autosomal recessive genetic disorder characterized by progressive bone marrow failure, multiple congenital abnormalities, and an increased risk of cancer. FA cells are characterized by chromosomal instability and hypersensitivity to DNA interstrand crosslinking agents. At least eight complementation groups exist (FA-A to G), and the genes for all of these except FA-B have been cloned. Functional linkage between the FA pathway and genes involved in susceptibility to breast cancer has been demonstrated by the interaction of the FANCA and FANCD2 proteins with BRCA1, and the discovery that the FANCD1 gene is identical to BRCA2. Here we have used the yeast two-hybrid system to test for direct interaction between BRCA2 or its effector RAD51 and the FANCA, FANCC and FANCG proteins. We found that FANCG was capable of binding to two separate sites in the BRCA2 protein, located either side of the BRC repeats. Furthermore, FANCG could be co-immunoprecipitated with BRCA2 from human cells, and FANCG co-localized in nuclear foci with both BRCA2 and RAD51 following DNA damage with mitomycin C. These results demonstrate that BRCA2 is directly connected to a pathway that is deficient in interstrand crosslink repair, and that at least one other FA protein is closely associated with the homologous recombination DNA repair machinery.
Hum Mol Genet 2003 Oct 01
PMID:Direct interaction of the Fanconi anaemia protein FANCG with BRCA2/FANCD1. 1291 60

Heterozygous carriers of mutations in the BRCA2 gene have a high risk of developing breast and other cancers. In these individuals, BRCA2 appears to act as a tumour suppressor gene, in that loss of the wild type allele is frequently observed within tumours, leading to loss of BRCA2 function. Because BRCA2 functions in DNA repair via homologous recombination, this leads to genomic instability. However, it is unclear whether loss of the wild type allele is stochastic or if heterozygosity for BRCA2 mutation carries a phenotype that contributes to tumorigenic progression. Here we demonstrate that, in a specific vertebrate cell type, the chicken B cell line DT40, heterozygosity for a BRCA2 mutation has a distinct phenotype. This is characterized by a reduced growth rate, increased cell death, heightened sensitivity to specific DNA damaging agents and reduced RAD51 focus formation after irradiation. Thus in certain cell types, genome instability might be driven directly by heterozygosity for BRCA2 mutation.
Hum Mol Genet 2003 Oct 15
PMID:Phenotypic effects of heterozygosity for a BRCA2 mutation. 1292 78

We have isolated a holoenzyme complex termed BRCC containing BRCA1, BRCA2, and RAD51. BRCC not only displays increased association with p53 following DNA damage but also ubiquitinates p53 in vitro. BRCC36 and BRCC45 are novel components of the complex with sequence homology to a subunit of the signalosome and proteasome complexes. Reconstitution of a recombinant four-subunit complex containing BRCA1/BARD1/BRCC45/BRCC36 revealed an enhanced E3 ligase activity compared to that of BRCA1/BARD1 heterodimer. In vivo, depletion of BRCC36 and BRCC45 by the small interfering RNAs (siRNAs) resulted in increased sensitivity to ionizing radiation and defects in G2/M checkpoint. BRCC36 shows aberrant expression in sporadic breast tumors. These findings identify BRCC as a ubiquitin E3 ligase complex that enhances cellular survival following DNA damage.
Mol Cell 2003 Nov
PMID:Regulation of BRCC, a holoenzyme complex containing BRCA1 and BRCA2, by a signalosome-like subunit and its role in DNA repair. 1463 69


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