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)

The Fanconi anemia (FA) pathway is responsible for interstrand crosslink repair. At the heart of this pathway is the FANCI-FAND2 (ID) complex, which, upon ubiquitination by the FA core complex, travels to sites of damage to coordinate repair that includes nucleolytic modification of the DNA surrounding the lesion and translesion synthesis. How the ID complex regulates these events is unknown. Here we describe a shRNA screen that led to the identification of two nucleases necessary for crosslink repair, FAN1 (KIAA1018) and EXDL2. FAN1 colocalizes at sites of DNA damage with the ID complex in a manner dependent on FAN1's ubiquitin-binding domain (UBZ), the ID complex, and monoubiquitination of FANCD2. FAN1 possesses intrinsic 5'-3' exonuclease activity and endonuclease activity that cleaves nicked and branched structures. We propose that FAN1 is a repair nuclease that is recruited to sites of crosslink damage in part through binding the ubiquitinated ID complex through its UBZ domain.
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PMID:A genetic screen identifies FAN1, a Fanconi anemia-associated nuclease necessary for DNA interstrand crosslink repair. 2070 Jan 43

DNase II is an endonuclease which plays a fundamental role in the degradation of DNA from both apoptotic cells, and nuclei extruded from red blood cells during erythropoiesis: important tasks, considering that everyday 10(8)-10(9) cells undergo apoptosis, and 10(11) red blood cells are produced in the adult human. The DNase II-null mouse demonstrates embryonic lethality due to type I interferon-mediated erythroid precursor cell death triggered by undegraded nucleic acids. However, the mechanisms leading to such cytotoxicity are poorly understood. A study in the current issue of the European Journal of Immunology investigates the role of the death ligand TRAIL in this process. Although TRAIL is shown to be dispensable for the interferon-induced apoptosis of erythroid cells in DNAse II(-/-) embryos, the authors have developed a useful strategy for further exploring this question in future studies. Interestingly, earlier studies by the same group showed that crossing the DNase II-null mouse with a mouse deficient for the type I interferon receptor can rescue the lethal anaemia observed in the DNase II-null embryos, but only at the cost of developing autoimmunity.
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PMID:The story of DNase II: a stifled death-wish leads to self-harm. 2070 89

The evolutionarily conserved SLX4 protein, a key regulator of nucleases, is critical for DNA damage response. SLX4 nuclease complexes mediate repair during replication and can also resolve Holliday junctions formed during homologous recombination. Here we describe the phenotype of the Btbd12 knockout mouse, the mouse ortholog of SLX4, which recapitulates many key features of the human genetic illness Fanconi anemia. Btbd12-deficient animals are born at sub-Mendelian ratios, have greatly reduced fertility, are developmentally compromised and are prone to blood cytopenias. Btbd12(-/-) cells prematurely senesce, spontaneously accumulate damaged chromosomes and are particularly sensitive to DNA crosslinking agents. Genetic complementation reveals a crucial requirement for Btbd12 (also known as Slx4) to interact with the structure-specific endonuclease Xpf-Ercc1 to promote crosslink repair. The Btbd12 knockout mouse therefore establishes a disease model for Fanconi anemia and genetically links a regulator of nuclease incision complexes to the Fanconi anemia DNA crosslink repair pathway.
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PMID:Disruption of mouse Slx4, a regulator of structure-specific nucleases, phenocopies Fanconi anemia. 2145 54

Homologous recombination (HR) is a mode of double-strand break (DSB) repair required for cell viability in vertebrate cells. Targeted integration of homologous DNA fragment by HR is usually a very rare event in vertebrate cells; however, in chicken B lymphoma cell line DT40, the ratio of targeted to random integration is extremely high. Although the underlying mechanism of this phenotype is not fully understood, DT40 has been utilized as a model cell line for a number of genetic analyses. Here we describe three assays for evaluating homologous recombinational repair (HRR) using DT40 as a model system, measuring gene-targeting frequency, analyzing HRR process of single DSB induced by yeast homing endonuclease I-SceI, and measuring sister chromatid exchange frequency. Combined with generation of gene-disrupted DT40 mutant cell line, these assays have been highly useful to investigate the mechanisms in HRR. Using these techniques, a role of HRR of not only Rad52 epistasis group genes but also genes whose mutation cause hereditary cancer syndrome, such as Fanconi anemia, has been established.
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PMID:Evaluation of homologous recombinational repair in chicken B lymphoma cell line, DT40. 2166 Jul 1

DNA interstrand cross-links (ICLs) pose a significant threat to genomic and cellular integrity by blocking essential cellular processes, including replication and transcription. In mammalian cells, much ICL repair occurs in association with DNA replication during S phase, following the stalling of a replication fork at the block caused by an ICL lesion. Here, we review recent work showing that the XPF-ERCC1 endonuclease and the hSNM1A exonuclease act in the same pathway, together with SLX4, to initiate ICL repair, with the MUS81-EME1 fork incision activity becoming important in the absence of the XPF-SNM1A-SLX4-dependent pathway. Another nuclease, the Fanconi anemia-associated nuclease (FAN1), has recently been implicated in the repair of ICLs, and we discuss the possible ways in which the activities of different nucleases at the ICL-stalled replication fork may be coordinated. In relation to this, we briefly speculate on the possible role of SLX4, which contains XPF and MUS81- interacting domains, in the coordination of ICL repair nucleases.
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PMID:Orchestrating the nucleases involved in DNA interstrand cross-link (ICL) repair. 2210 40

The endonuclease complex Ercc1/Xpf is involved in interstrand crosslink repair and functions downstream of the Fanconi pathway. Loss of Ercc1 causes hematopoietic defects similar to those seen in Fanconi Anemia. Ercc1(-/-) mice die 3-4 weeks after birth, which prevents long-term follow up of the hematopoietic compartment. We used alternative Ercc1 mouse models to examine the effect of low or absent Ercc1 activity on hematopoiesis. Tie2-Cre-driven deletion of a floxed Ercc1 allele was efficient (>80%) in fetal liver hematopoietic cells. Hematopoietic stem and progenitor cells (HSPCs) with a deleted allele were maintained in mice up to 1 year of age when harboring a wt allele, but were progressively outcompeted when the deleted allele was combined with a knockout allele. Mice with a minimal Ercc1 activity expressed by 1 or 2 hypomorphic Ercc1 alleles have an extended life expectancy, which allows analysis of HSPCs at 10 and 20 weeks of age. The HSPC compartment was affected in all Ercc1-deficient models. Actively proliferating multipotent progenitors were most affected as were myeloid and erythroid clonogenic progenitors. In conclusion, lack of Ercc1 results in a severe competitive disadvantage of HSPCs and is most deleterious in proliferating progenitor cells.
Anemia 2012
PMID:Loss of ercc1 results in a time- and dose-dependent reduction of proliferating early hematopoietic progenitors. 2270 Nov 68

Chicken anaemia virus (CAV) is an economically important pathogen of chickens with worldwide distribution. CAV is the causative agent of chicken anaemia disease, causing severe anaemia, lymphoid atrophy and immunosuppression in young birds. In the present study, the genetic variation of circulating CAVs in west Azerbaijan broiler farms was investigated and compared with CAVs from other countries. Extracted viral DNA from livers of chickens positive for CAV (46 out of 100) was used and a fragment of the VP1 gene 1390 base pairs in size was amplified. The purified products were subjected to restriction fragment-length polymorphism (RFLP) using HinfI endonuclease and nucleotide sequencing. Four different RFLP patterns were identified from all examined CAV DNAs. Sequence analysis of the VP1 gene of isolated CAV viruses revealed a high genetic distance (0.5 to 4.7%) among CAV isolates. Phylogenetic analysis showed that CAVs isolated from Iranian poultry farms clustered with CAVs isolated from different parts of the world. It was concluded that the circulating CAVs in broiler farms of west Azerbaijan had a high genomic variation.
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PMID:Molecular characterization of the chicken anaemia viruses isolated from broiler farms of west Azerbaijan, Iran. 2358 37

Fanconi anemia (FA) is a rare genomic instability disorder characterized by progressive bone marrow failure and predisposition to cancer. FA-associated gene products are involved in the repair of DNA interstrand crosslinks (ICLs). Fifteen FA-associated genes have been identified, but the genetic basis in some individuals still remains unresolved. Here, we used whole-exome and Sanger sequencing on DNA of unclassified FA individuals and discovered biallelic germline mutations in ERCC4 (XPF), a structure-specific nuclease-encoding gene previously connected to xeroderma pigmentosum and segmental XFE progeroid syndrome. Genetic reversion and wild-type ERCC4 cDNA complemented the phenotype of the FA cell lines, providing genetic evidence that mutations in ERCC4 cause this FA subtype. Further biochemical and functional analysis demonstrated that the identified FA-causing ERCC4 mutations strongly disrupt the function of XPF in DNA ICL repair without severely compromising nucleotide excision repair. Our data show that depending on the type of ERCC4 mutation and the resulting balance between both DNA repair activities, individuals present with one of the three clinically distinct disorders, highlighting the multifunctional nature of the XPF endonuclease in genome stability and human disease.
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PMID:Mutations in ERCC4, encoding the DNA-repair endonuclease XPF, cause Fanconi anemia. 2362 86

Orthomyxovirus Influenza A virus (IAV) heterotrimeric polymerase performs transcription of viral mRNAs by cap-snatching, which involves generation of capped primers by host pre-mRNA binding via the PB2 subunit cap-binding site and cleavage 10-13 nucleotides from the 5' cap by the PA subunit endonuclease. Thogotoviruses, tick-borne orthomyxoviruses that includes Thogoto (THOV), Dhori (DHOV) and Jos (JOSV) viruses, are thought to perform cap-snatching by cleaving directly after the cap and thus have no heterogeneous, host-derived sequences at the 5' extremity of their mRNAs. Based on recent work identifying the cap-binding and endonuclease domains in IAV polymerase, we determined the crystal structures of two THOV PB2 domains, the putative cap-binding and the so-called '627-domain', and the structures of the putative endonuclease domains (PA-Nter) of THOV and DHOV. Despite low sequence similarity, corresponding domains have the same fold confirming the overall architectural similarity of orthomyxovirus polymerases. However the putative Thogotovirus cap-snatching domains in PA and PB2 have non-conservative substitutions of key active site residues. Biochemical analysis confirms that, unlike the IAV domains, the THOV and DHOV PA-Nter domains do not bind divalent cations and have no endonuclease activity and the THOV central PB2 domain does not bind cap analogues. On the other hand, sequence analysis suggests that other, non-influenza, orthomyxoviruses, such as salmon anemia virus (isavirus) and Quaranfil virus likely conserve active cap-snatching domains correlating with the reported occurrence of heterogeneous, host-derived sequences at the 5' end of the mRNAs of these viruses. These results highlight the unusual nature of transcription initiation by Thogotoviruses.
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PMID:Comparative structural and functional analysis of orthomyxovirus polymerase cap-snatching domains. 2445 73

Fanconi anaemia complementation group M protein (FANCM), a component of the human Fanconi anemia pathway, acts as DNA translocase that is essential during the repair of DNA interstrand cross-links. The DNA-damage-binding function of FANCM is strongly enhanced by the histone fold-containing FANCM-associated protein MHF1. We identified a single homologue of MHF1 in the genome of Arabidopsis thaliana. Similar to the loss of AtFANCM, the loss of AtMHF1 leads to several meiotic defects, such as chromosome bridges between bivalents and an unequal distribution of chromosomes. Moreover, MHF1, together with FANCM, is involved in interstrand cross-link repair in plants. This phenotype is detectable only in double mutants of the RecQ helicase and BLM homologue RECQ4A, which appears to function in a parallel pathway to the FANCM/MHF1 complex. However, in somatic cells, FANCM has an MHF1-independent function in replicative repair in a parallel pathway to the endonuclease MUS81. Furthermore, MHF1 is required for efficient somatic homologous recombination (HR) - a role antagonistic to FANCM. FANCM and RECQ4A define two parallel pathways of HR suppression in Arabidopsis. Hyperrecombination in the fancm but not the recq4A mutant can be abolished by MHF1 mutations. This finding indicates that MHF1 and FANCM act at different steps of a single, common, HR pathway.
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PMID:MHF1 plays Fanconi anaemia complementation group M protein (FANCM)-dependent and FANCM-independent roles in DNA repair and homologous recombination in plants. 2463 47


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