Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.1.30.2 (endonuclease)
18,621 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Dent's disease is an X-linked renal tubular disorder characterized by low-molecular-weight proteinuria, hypercalciuria, nephrocalcinosis, nephrolithiasis, and renal failure. Patients with Dent's disease may also suffer from rickets and other features of the renal Fanconi Syndrome. Patients may have mutations in the X-linked renal chloride channel gene, CLCN5, which encodes a 746-amino-acid protein with 12-13 transmembrane domains. We have investigated the 11 coding exons of CLCN5 for mutations in eight unrelated patients with Dent's disease. Leukocyte DNA was used for the polymerase chain reaction amplification of CLCN5 and the products analyzed for single-stranded conformational polymorphisms (SSCPs). Abnormal SSCPs were sequenced and revealed eight mutations. These consisted of three nonsense mutations (Arg34Stop, Arg648Stop, Arg704Stop), four deletions involving codons 40, 86, 157, and 241, and one acceptor splice consensus sequence mutation tgcag --> tgaag. The mutations were confirmed either by restriction endonuclease or sequence-specific oligonucleotide hybridization analysis. In addition, an analysis of 110 alleles from 74 unrelated normal individuals demonstrated that the DNA sequence changes were not common polymorphisms. All of the mutations predict truncated chloride channels that are likely to result in a functional loss. Thus, our findings expand the spectrum of CLCN5 mutations associated with Dent's disease and the results will help to elucidate further the functional domains of this novel chloride channel.
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PMID:Renal chloride channel, CLCN5, mutations in Dent's disease. 1046 81

Cells harvested from Fanconi anemia (FA) patients show an increased hypersensitivity to the multifunctional DNA damaging agent mitomycin C (MMC), which causes cross-links in DNA as well as 7,8-dihydro-8-oxoguanine (8-oxoG) adducts indicative of escalated oxidative DNA damage. We show here that the Drosophila multifunctional S3 cDNA, which encodes an N-glycosylase/apurinic/apyrimidinic (AP) lyase activity was found to correct the FA Group A (FA(A)) and FA Group C (FA(C)) sensitivity to MMC and hydrogen peroxide (H2O2). Furthermore, the Drosophila S3 cDNA was shown to protect AP endonuclease deficient E. coli cells against H(2)O(2) and MMC, and also protect 8-oxoG repair deficient mutM E. coli strains against MMC and H2O2 cell toxicity. Conversely, the human S3 protein failed to complement the AP endonuclease deficient E. coli strain, most likely because it lacks N-glycosylase activity for the repair of oxidatively-damaged DNA bases. Although the human S3 gene is clearly not the genetic alteration in FA cells, our results suggest that oxidative DNA damage is intimately involved in the overall FA phenotype, and the cytotoxic effect of selective DNA damaging agents in FA cells can be overcome by trans-complementation with specific DNA repair cDNAs. Based on these findings, we would predict other oxidative repair proteins, or oxidative scavengers, could serve as protective agents against the oxidative DNA damage that occurs in FA.
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PMID:The Drosophila S3 multifunctional DNA repair/ribosomal protein protects Fanconi anemia cells against oxidative DNA damaging agents. 1118 42

Fanconi anemia (FA) is an autosomal recessive disorder associated with pancytopenia and cancer susceptibility. The disorder is heterogeneous, with at least nine complementation groups having been identified. Several recent studies have suggested that defective plasmid DNA end-joining is a consistent feature of FA cells. It was therefore surprising to discover a strain of fibroblasts from an FA patient that possessed wild-type plasmid DNA end-joining activity. Unlike other FA strains, these fibroblasts have wild-type levels of homologous DNA recombination activity and are relatively insensitive to restriction endonuclease-induced death. Interestingly, while end-joining in a number of FA fibroblast strains belonging to complementation groups A, C, and D2 was approximately 70% precise, end-joining in this latter strain of fibroblasts was more than 95% imprecise. Analysis revealed that these latter cells harbored an allele of the FA C gene, referred to as 322delG, that encodes an amino-terminal truncated protein. The relative rarity of this allele precluded the analysis of other FA fibroblast strains; however, studies revealed that overexpression of this allele in normal cells recapitulated the DNA end-joining phenotype seen in the 322delG FA fibroblast strain. These results indicate that DNA end-joining in fibroblasts expressing the 322delG allele of the FA-C gene in fibroblasts is highly imprecise; however, the DNA repair efficiency of these cells is more normal than that commonly associated with FA fibroblasts. This conclusion is intriguing, since a number of reports have suggested that patients harboring this allele exhibit a milder clinical course than do individuals with other alleles of the FA-C gene.
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PMID:Intermediate DNA repair activity associated with the 322delG allele of the fanconi anemia complementation group C gene. 1536 73

The genetically complex disease Fanconi anemia (FA) comprises cancer predisposition, developmental defects, and bone marrow failure due to elevated apoptosis. The FA cellular phenotype includes universal sensitivity to DNA crosslinking damage, symptoms of oxidative stress, and reduced mutability at the X-linked HPRT gene. In this review article, we present a new heuristic molecular model that accommodates these varied features of FA cells. In our view, the FANCA, -C, and -G proteins, which are both cytoplasmic and nuclear, have an integrated dual role in which they sense and convey information about cytoplasmic oxidative stress to the nucleus, where they participate in the further assembly and functionality of the nuclear core complex (NCCFA= FANCA/B/C/E/F/G/L). In turn, NCCFA facilitates DNA replication at sites of base damage and strand breaks by performing the critical monoubiquitination of FANCD2, an event that somehow helps stabilize blocked and broken replication forks. This stabilization facilitates two kinds of processes: translesion synthesis at sites of blocking lesions (e.g., oxidative base damage), which produces point mutations by error-prone polymerases, and homologous recombination-mediated restart of broken forks, which arise spontaneously and when crosslinks are unhooked by the ERCC1-XPF endonuclease. In the absence of the critical FANCD2 monoubiquitination step, broken replication forks further lose chromatid continuity by collapsing into a configuration that is more difficult to restart through recombination and prone to aberrant repair through nonhomologous end joining. Thus, the FA regulatory pathway promotes chromosome integrity by monitoring oxidative stress and coping efficiently with the accompanying oxidative DNA damage during DNA replication.
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PMID:How Fanconi anemia proteins promote the four Rs: replication, recombination, repair, and recovery. 1566 41

The ERCC1-XPF heterodimer is a structure-specific endonuclease involved in both nucleotide excision repair and interstrand crosslink repair. Mice carrying a genetic defect in Ercc1 display symptoms suggestive of a progressive, segmental progeria, indicating that disruption of one or both of these DNA damage repair pathways accelerates aging. In the hematopoietic system, there are defined age-associated changes for which the cause is unknown. To determine if DNA repair is critical to prolonged hematopoietic function, hematopoiesis in Ercc1-/- mice was compared to that in young and old wild-type mice. Ercc1-/- mice (3-week-old) exhibited multilineage cytopenia and fatty replacement of bone marrow, similar to old wild-type mice. In addition, the proliferative reserves of hematopoietic progenitors and stress erythropoiesis were significantly reduced in Ercc1-/- mice compared to age-matched controls. These features were not seen in nucleotide excision repair-deficient Xpa-/- mice, but are characteristic of Fanconi anemia, a human cancer syndrome caused by defects in interstrand crosslink repair. These data support the hypothesis that spontaneous interstrand crosslink damage contributes to the functional decline of the hematopoietic system associated with aging.
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PMID:Reduced hematopoietic reserves in DNA interstrand crosslink repair-deficient Ercc1-/- mice. 1569 71

The helicase-associated endonuclease for fork-structured DNA (Hef) is an archaeabacterial protein that processes blocked replication forks. Here we have isolated the vertebrate Hef ortholog and investigated its molecular function. Disruption of this gene in chicken DT40 cells results in genomic instability and sensitivity to DNA cross-links. The similarity of this phenotype to that of cells lacking the Fanconi anemia-related (FA) tumor-suppressor genes led us to investigate whether Hef functions in this pathway. Indeed, we found a genetic interaction between the FANCC and Hef genes. In addition, Hef is a component of the FA nuclear protein complex that facilitates its DNA damage-inducible chromatin localization and the monoubiquitination of the FA protein FANCD2. Notably, Hef interacts directly with DNA structures that are intermediates in DNA replication. This discovery sheds light on the origins, regulation and molecular function of the FA tumor-suppressor pathway in the maintenance of genome stability.
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PMID:The vertebrate Hef ortholog is a component of the Fanconi anemia tumor-suppressor pathway. 1611 34

Fanconi anemia (FA) is a multigenic recessive disease resulting in bone marrow failure and increased cancer susceptibility. Cells from FA patients and mouse models are sensitive to DNA interstrand crosslinks (ICLs) and FA mice are moderately sensitive to ionizing radiation (IR). Both kinds of damage induce DNA double strand breaks (DSBs). To date, nine genes in 11 complementation groups have been identified; however, the precise function of the FA pathway remains unclear. Many of the proteins form a nuclear complex necessary for the mono-ubiquitination of the downstream protein, Fancd2. To further investigate the role of the FA pathway in repair of DSBs, we generated Fancd2(-/-)/Prkdc(sc/sc) double mutant mice. Prkdc(sc/sc) mutant mice have a defect in non-homologous end joining (NHEJ) and are sensitive to IR-induced DNA damage. Double mutant animals and primary cells were more sensitive to IR than either single mutant, suggesting that Fancd2 operates in DSB repair pathway distinct from NHEJ. Fancd2(-/-)/Prkdc(sc/sc) double mutant cells were also more sensitive to DSBs generated by a restriction endonuclease. The role of Fancd2 in DSB repair may account for the moderate sensitivity of FA cells to irradiation and FA cells sensitivity to ICLs that are repaired via a DSB intermediate.
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PMID:Fancd2 functions in a double strand break repair pathway that is distinct from non-homologous end joining. 1613 54

FAAP24, a new XPF endonuclease family member identified by in a recent issue of Molecular Cell, heterodimerizes with FANCM, binds unwound DNA, and reveals how the Fanconi anemia core complex concentrates DNA repair proteins at stalled replication forks.
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PMID:The Fanconi anemia signalosome anchor. 1728 82

DNA interstrand cross-linking agents have been widely used in chemotherapeutic treatment of cancer. The majority of interstrand cross-links (ICLs) in mammalian cells are removed via a complex process that involves the formation of double-strand breaks at replication forks, incision of the ICL, and subsequent error-free repair by homologous recombination. How double-strand breaks effect the removal of ICLs and the downstream homologous recombination process is not clear. Here, we describe a plasmid-based recombination assay in which one copy of the CFP gene is inactivated by a site-specific psoralen ICL and can be repaired by gene conversion with a mutated homologous donor sequence. We found that the homology-dependent recombination (HDR) is inhibited by the ICL. However, when we introduced a double-strand break adjacent to the site of the ICL, the removal of the ICL was enhanced and the substrate was funneled into a HDR repair pathway. This process was not dependent on the nucleotide excision repair pathway, but did require the ERCC1-XPF endonuclease and REV3. In addition, both the Fanconi anemia pathway and the mismatch repair protein MSH2 were required for the recombinational repair processing of the ICL. These results suggest that the juxtaposition of an ICL and a DSB stimulates repair of ICLs through a process requiring components of mismatch repair, ERCC1-XPF, REV3, Fanconi anemia proteins, and homologous recombination repair factors.
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PMID:Double-strand breaks induce homologous recombinational repair of interstrand cross-links via cooperation of MSH2, ERCC1-XPF, REV3, and the Fanconi anemia pathway. 1766 95

Recent studies suggest a crucial role for homologous recombination (HR) in repairing replication-associated DNA lesions. In mammals, the Mus81 endonuclease and the Fanconi anemia (FA) pathway have been implicated in HR repair; however, their functional relationship has remained unexplored. Here, we knockout the genes for Mus81 and FANCB, a component of the FA core complex, in the human Nalm-6 cell line. We show that Mus81 plays an important role in cell proliferation to suppress cell death when FANCB is missing, indicating a functional linkage between Mus81 and the FA pathway. In DNA cross-link repair, roles for Mus81 and the FA pathway appear to have an overlapping function. Intriguingly, Mus81 and FANCB act independently in surviving exposure to camptothecin (CPT). Although CPT-induced FANCD2 and Mus81 foci co-localize with Rad51, loss of Mus81, but not FANCB, results in significantly decreased levels of spontaneous and CPT-induced sister chromatid exchanges (SCEs). In addition, Mus81, unlike FANCB, has no significant role in gene targeting as well as in repairing hydroxyurea (HU)-induced stalls of replication forks. Collectively, our results provide the first evidence for differential functions of Mus81 and the FA pathway in repair of DNA damage during replication in human cells.
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PMID:Human Mus81 and FANCB independently contribute to repair of DNA damage during replication. 1790 71


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